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Abstract:

An object of the present invention is to synthesize a novel
1,2,3,4-tetrahydroquinoxaline derivative represented by formula (1) and
to find a pharmacological action of the derivative. In the formula, the
R1 represents a halogen, an alkyl, cycloalkyl, aryl or heterocyclic
group, or the like; p represents 0 to 5; R2 represents a halogen, an
alkyl, hydroxyl or alkoxy group, or the like; q represents 0 to 2;
R3 represents hydrogen, an alkyl, alkenyl, alkylcarbonyl or
arylcarbonyl group, or the like; R4 and R5 independently
represent hydrogen, a halogen, an alkyl, alkenyl, alkynyl, cycloalkyl,
aryl or heterocyclic group, or the like; R6 represents hydrogen, an
alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclic group, or the
like; A represents an alkylene; R7 represents OR8,
NR8R9, SR8, S(O)R8, S(O)2R8; and X
represents O or S.
##STR00001##

Claims:

1. A compound represented by the following general formula (1) or a salt
thereof: ##STR00366## [wherein R1 represents a halogen atom, a lower
alkyl group which may have at least a substituent, a lower cycloalkyl
group which may have at least a substituent, an aryl group which may have
at least a substituent, a heterocyclic group which may have at least a
substituent, a hydroxy group, an ester of a hydroxy group, a lower alkoxy
group which may have at least a substituent, a lower cycloalkyloxy group
which may have at least a substituent, an aryloxy group which may have at
least a substituent, a heterocyclic oxy group which may have at least a
substituent, a mercapto group, an ester of a mercapto group, a lower
alkylthio group which may have at least a substituent, a lower
cycloalkylthio group which may have at least a substituent, an arylthio
group which may have at least a substituent, a heterocyclic thio group
which may have at least a substituent, an amino group, a lower alkylamino
group which may have at least a substituent, a lower cycloalkylamino
group which may have at least a substituent, an arylamino group which may
have at least a substituent, a heterocyclic amino group which may have at
least a substituent, an amide of an amino group, an amide of a lower
alkylamino group which may have at least a substituent, an amide of a
lower cycloalkylamino group which may have at least a substituent, an
amide of an arylamino group which may have at least a substituent, an
amide of a heterocyclic amino group which may have at least a
substituent, a formyl group, a lower alkylcarbonyl group which may have
at least a substituent, a lower cycloalkylcarbonyl group which may have
at least a substituent, an arylcarbonyl group which may have at least a
substituent, a heterocyclic carbonyl group which may have at least a
substituent, a carboxy group, an ester of a carboxy group, an amide of a
carboxy group, a lower alkylsulfonyl group which may have at least a
substituent, a lower cycloalkylsulfonyl group which may have at least a
substituent, an arylsulfonyl group which may have at least a substituent,
a heterocyclic sulfonyl group which may have at least a substituent, a
sulfonic acid group, an ester of a sulfonic acid group, an amide of a
sulfonic acid group, a nitro group or a cyano group;p represents an
integer of 0 to 5;in the case where p is 2 to 5, each R1 may be the
same or different;R2 represents a halogen atom, a lower alkyl group
which may have at least a substituent, a hydroxy group, an ester of a
hydroxy group or a lower alkoxy group which may have at least a
substituent;q represents an integer of 0 to 2;in the case where q is 2,
each R2 may be the same or different;R3 represents a hydrogen
atom, a lower alkyl group which may have at least a substituent, a lower
alkenyl group which may have at least a substituent, a lower
alkylcarbonyl group which may have at least a substituent, a lower
alkenylcarbonyl group which may have at least a substituent or an
arylcarbonyl group which may have at least a substituent;R4 and
R5 may be the same or different and represent a hydrogen atom, a
halogen atom, a lower alkyl group which may have at least a substituent,
a lower alkenyl group which may have at least a substituent, a lower
alkynyl group which may have at least a substituent, a lower cycloalkyl
group which may have at least a substituent, an aryl group which may have
at least a substituent or a heterocyclic group which may have at least a
substituent;R4 and R5 may be combined together to form a 3- to
8-membered lower cycloalkane ring which may have at least a
substituent;R6 represents a hydrogen atom, a lower alkyl group which
may have at least a substituent, a lower alkenyl group which may have at
least a substituent, a lower alkynyl group which may have at least a
substituent, a lower cycloalkyl group which may have at least a
substituent, an aryl group which may have at least a substituent or a
heterocyclic group which may have at least a substituent;A represents a
lower alkylene group which may have at least a substituent;R7
represents OR8, NR8R9, SR8, S(O)R8 or
S(O)2R8;R8 and R9 may be the same or different and
represent a hydrogen atom, a lower alkyl group which may have at least a
substituent, a lower alkenyl group which may have at least a substituent,
a lower alkynyl group which may have at least a substituent, a lower
cycloalkyl group which may have at least a substituent, an aryl group
which may have at least a substituent, a heterocyclic group which may
have at least a substituent, a formyl group, a lower alkylcarbonyl group
which may have at least a substituent, a lower alkenylcarbonyl group
which may have at least a substituent, a lower alkynylcarbonyl group
which may have at least a substituent, a lower cycloalkylcarbonyl group
which may have at least a substituent, an arylcarbonyl group which may
have at least a substituent, a heterocyclic carbonyl group which may have
at least a substituent, a carboxy group, a lower alkoxycarbonyl group
which may have at least a substituent, a lower alkenyloxycarbonyl group
which may have at least a substituent, a lower alkynyloxycarbonyl group
which may have at least a substituent, a lower cycloalkyloxycarbonyl
group which may have at least a substituent, an aryloxycarbonyl group
which may have at least a substituent, a heterocyclic oxycarbonyl group
which may have at least a substituent, a lower alkylsulfonyl group which
may have at least a substituent, a lower alkenylsulfonyl group which may
have at least a substituent, a lower alkynylsulfonyl group which may have
at least a substituent, a lower cycloalkylsulfonyl group which may have
at least a substituent, an arylsulfonyl group which may have at least a
substituent, a heterocyclic sulfonyl group which may have at least a
substituent, an aminocarbonyl group, a lower alkylaminocarbonyl group
which may have at least a substituent, a lower alkenylaminocarbonyl group
which may have at least a substituent, a lower alkynylaminocarbonyl group
which may have at least a substituent, a lower cycloalkylaminocarbonyl
group which may have at least a substituent, an arylaminocarbonyl group
which may have at least a substituent or a heterocyclic aminocarbonyl
group which may have at least a substituent;in the case where R7 is
NR8R9, R8 and R9 may be combined together to form a
3- to 8-membered nitrogen-containing heterocyclic ring which may have at
least a substituent; andX represents O or S].

2. The compound or a salt thereof according to claim 1, wherein in the
general formula (1), R1 represents a halogen atom, a lower alkyl
group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a
hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower
cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a
mercapto group, an ester of a mercapto group, a lower alkylthio group, a
lower cycloalkylthio group, an arylthio group, a heterocyclic thio group,
an amino group, a lower alkylamino group, a lower cycloalkylamino group,
an arylamino group, a heterocyclic amino group, an amide of an amino
group, an amide of a lower alkylamino group, an amide of a lower
cycloalkylamino group, an amide of an arylamino group, an amide of a
heterocyclic amino group, a lower alkylcarbonyl group, a lower
cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl
group, a carboxy group, an ester of a carboxy group, an amide of a
carboxy group, a lower alkylsulfonyl group, a lower cycloalkylsulfonyl
group, an arylsulfonyl group, a heterocyclic sulfonyl group, a sulfonic
acid group, an ester of a sulfonic acid group, an amide of a sulfonic
acid group, a nitro group or a cyano group;in the case where R1 is a
lower alkyl group, a lower alkoxy group, a lower alkylthio group, a lower
alkylamino group, an amide of a lower alkylamino group, a lower
alkylcarbonyl group or a lower alkylsulfonyl group, the lower alkyl
group, lower alkoxy group, lower alkylthio group, lower alkylamino group,
amide of a lower alkylamino group, lower alkylcarbonyl group or lower
alkylsulfonyl group may have one or a plurality of groups selected from a
halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic
group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy
group, a lower alkoxy group substituted with at least a halogen atom, a
lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a
lower alkylthio group, a lower cycloalkylthio group, an arylthio group, a
heterocyclic thio group, an amino group, a lower alkylamino group, a
lower cycloalkylamino group, an arylamino group, a heterocyclic amino
group, an amide of an amino group, an amide of a lower alkylamino group,
an amide of a lower cycloalkylamino group, an amide of an arylamino
group, an amide of a heterocyclic amino group, a lower alkylcarbonyl
group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a
heterocyclic carbonyl group, a carboxy group, an ester of a carboxy
group, an amide of a carboxy group, a lower alkylsulfonyl group, a lower
cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl
group, a sulfonic acid group, an ester of a sulfonic acid group, an amide
of a sulfonic acid group, a nitro group and a cyano group as
substituents;in the case where R1 is a lower cycloalkyl group, an
aryl group, a heterocyclic group, a lower cycloalkyloxy group, an aryloxy
group, a heterocyclic oxy group, a lower cycloalkylthio group, an
arylthio group, a heterocyclic thio group, a lower cycloalkylamino group,
an arylamino group, a heterocyclic amino group, an amide of a lower
cycloalkylamino group, an amide of an arylamino group, an amide of a
heterocyclic amino group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a lower
cycloalkylsulfonyl group, an arylsulfonyl group or a heterocyclic
sulfonyl group, the lower cycloalkyl group, aryl group, heterocyclic
group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group,
lower cycloalkylthio group, arylthio group, heterocyclic thio group,
lower cycloalkylamino group, arylamino group, heterocyclic amino group,
amide of a lower cycloalkylamino group, amide of an arylamino group,
amide of a heterocyclic amino group, lower cycloalkylcarbonyl group,
arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkylsulfonyl
group, arylsulfonyl group or heterocyclic sulfonyl group may have one or
a plurality of groups selected from a halogen atom, a lower alkyl group,
a lower alkyl group substituted with at least a halogen atom, a hydroxy
group, an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy
group substituted with at least a halogen atom, a lower alkylthio group,
an amino group, a lower alkylamino group, an amide of an amino group, an
amide of a lower alkylamino group, a lower alkylcarbonyl group, a carboxy
group, an ester of a carboxy group, an amide of a carboxy group, a lower
alkylsulfonyl group, a sulfonic acid group, an ester of a sulfonic acid
group, an amide of a sulfonic acid group, a nitro group and a cyano group
as substituents;p represents an integer of 0 to 3;in the case where p is
2 or 3, each R1 may be the same or different;R2 represents a
halogen atom, a lower alkyl group, a hydroxy group or a lower alkoxy
group;q represents an integer of 0 to 2;in the case where q is 2, each
R2 may be the same or different;R3 represents a hydrogen atom,
a lower alkyl group, a lower alkenyl group, a lower alkylcarbonyl group,
a lower alkenylcarbonyl group or an arylcarbonyl group;in the case where
R3 is a lower alkyl group or a lower alkylcarbonyl group, the lower
alkyl group or lower alkylcarbonyl group may have one or a plurality of
groups selected from a halogen atom and an aryl group as substituents;in
the case where R3 is an arylcarbonyl group, the arylcarbonyl group
may have one or a plurality of groups selected from a halogen atom, a
lower alkyl group, a lower alkyl group substituted with at least a
halogen atom, a lower alkoxy group and a lower alkoxy group substituted
with at least a halogen atom as substituents;R4 and R5 may be
the same or different and represent a hydrogen atom, a halogen atom, a
lower alkyl group, a lower cycloalkyl group, aryl or a heterocyclic
group;in the case where R4 or R5 is a lower alkyl group, the
lower alkyl group may have one or a plurality of groups selected from a
halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic
group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy
group, a lower alkoxy group substituted with at least a halogen atom, a
lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a
lower alkylthio group, a lower cycloalkylthio group, an arylthio group, a
heterocyclic thio group, an amino group, a lower alkylamino group, a
lower cycloalkylamino group, an arylamino group, a heterocyclic amino
group, an amide of an amino group, an amide of a lower alkylamino group,
an amide of a lower cycloalkylamino group, an amide of an arylamino
group, an amide of a heterocyclic amino group, a lower alkylcarbonyl
group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a
heterocyclic carbonyl group, a carboxy group, an ester of a carboxy
group, an amide of a carboxy group, a nitro group and a cyano group as
substituents;in the case where R1 or R5 is a lower cycloalkyl
group, aryl or a heterocyclic group, the lower cycloalkyl group, aryl or
heterocyclic group may have one or a plurality of groups selected from a
halogen atom, a lower alkyl group, a lower alkyl group substituted with
at least a halogen atom, a hydroxy group, an ester of a hydroxy group, a
lower alkoxy group, a lower alkoxy group substituted with at least a
halogen atom, a lower alkylthio group, an amino group, a lower alkylamino
group, an amide of an amino group, an amide of a lower alkylamino group,
a lower alkylcarbonyl group, a carboxy group, an ester of a carboxy
group, an amide of a carboxy group, a lower alkylsulfonyl group, a
sulfonic acid group, an ester of a sulfonic acid group, an amide of a
sulfonic acid group, a nitro group and a cyano group as
substituents;R4 and R5 may be combined together to form a 3- to
8-membered lower cycloalkane ring;R6 represents a hydrogen atom, a
lower alkyl group, a lower alkenyl group, a lower alkynyl group or a
lower cycloalkyl group;in the case where R6 is a lower alkyl group,
a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group,
the lower alkyl group, lower alkenyl group, lower alkynyl group or lower
cycloalkyl group may have one or a plurality of groups selected from a
halogen atom and an aryl group as substituents;A represents a lower
alkylene group which may be substituted with at least a hydroxy group or
a halogen atom;R7 represents OR8, NR8R9 or
SR8;R8 and R9 may be the same or different and represent a
hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower cycloalkyl group, an aryl group, a heterocyclic
group, a formyl group, a lower alkylcarbonyl group, a lower
alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower
cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl
group, a carboxy group, a lower alkoxycarbonyl group, a lower
alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, a lower
cycloalkyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclic
oxycarbonyl group, a lower alkylsulfonyl group, a lower alkenylsulfonyl
group, a lower alkynylsulfonyl group, a lower cycloalkylsulfonyl group,
an arylsulfonyl group, a heterocyclic sulfonyl group, an aminocarbonyl
group, a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl
group, a lower alkynylaminocarbonyl group, a lower
cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a
heterocyclic aminocarbonyl group;in the case where R8 or R9 is
a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower
alkynylcarbonyl group, a lower alkoxycarbonyl group, a lower
alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, a lower
alkylsulfonyl group, a lower alkenylsulfonyl group, a lower
alkynylsulfonyl group, a lower alkylaminocarbonyl group, a lower
alkenylaminocarbonyl group or a lower alkynylaminocarbonyl group, the
lower alkyl group, lower alkenyl group, lower alkynyl group, lower
alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl
group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower
alkynyloxycarbonyl group, lower alkylsulfonyl group, lower
alkenylsulfonyl group, lower alkynylsulfonyl group, lower
alkylaminocarbonyl group, lower alkenylaminocarbonyl group or lower
alkynylaminocarbonyl group may have one or a plurality of groups selected
from a halogen atom, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower
alkoxy group, a lower alkoxy group substituted with at least a halogen
atom, a lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy
group, a lower alkylthio group, a lower cycloalkylthio group, an arylthio
group, a heterocyclic thio group, an amino group, a lower alkylamino
group, a lower cycloalkylamino group, an arylamino group, a heterocyclic
amino group, an amide of an amino group, an amide of a lower alkylamino
group, an amide of a lower cycloalkylamino group, an amide of an
arylamino group, an amide of a heterocyclic amino group, a lower
alkylcarbonyl group, a lower cycloalkylcarbonyl group, an arylcarbonyl
group, a heterocyclic carbonyl group, a carboxy group, an ester of a
carboxy group, an amide of a carboxy group, a lower alkylsulfonyl group,
a lower cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic
sulfonyl group, a sulfonic acid group, an ester of a sulfonic acid group,
an amide of a sulfonic acid group, a nitro group and a cyano group as
substituents;in the case where R8 or R9 is a lower cycloalkyl
group, an aryl group, a heterocyclic group, a lower cycloalkylcarbonyl
group, an arylcarbonyl group, a heterocyclic carbonyl group, a lower
cycloalkyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclic
oxycarbonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl
group, a heterocyclic sulfonyl group, a lower cycloalkylaminocarbonyl
group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group,
the lower cycloalkyl group, aryl group, heterocyclic group, lower
cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl
group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group,
heterocyclic oxycarbonyl group, lower cycloalkylsulfonyl group,
arylsulfonyl group, heterocyclic sulfonyl group, lower
cycloalkylaminocarbonyl group, arylaminocarbonyl group or heterocyclic
aminocarbonyl group may have one or a plurality of groups selected from a
halogen atom, a lower alkyl group, a lower alkyl group substituted with
at least a halogen atom, a lower alkyl group substituted with at least a
hydroxy group, a lower alkenyl group, a lower alkynyl group, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group,
an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group
substituted with at least a halogen atom, a lower alkenyloxy group, a
lower alkynyloxy group, a lower cycloalkyloxy group, an aryloxy group, a
heterocyclic oxy group, a lower alkylthio group, a lower cycloalkylthio
group, an arylthio group, a heterocyclic thio group, an amino group, a
lower alkylamino group, a lower cycloalkylamino group, an arylamino
group, a heterocyclic amino group, an amide of an amino group, an amide
of a lower alkylamino group, an amide of a lower cycloalkylamino group,
an amide of an arylamino group, an amide of a heterocyclic amino group, a
lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a carboxy group, an
ester of a carboxy group, an amide of a carboxy group, a lower
alkylsulfonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl
group, a heterocyclic sulfonyl group, a sulfonic acid group, an ester of
a sulfonic acid group, an amide of a sulfonic acid group, a nitro group
and a cyano group as substituents;in the case where R7 is
NR8R9, R8 and R9 may be combined together to form a
5- or 6-membered nitrogen-containing heterocyclic ring; andX represents O
or S.

3. The compound or a salt thereof according to claim 1, wherein in the
general formula (1), R1 represents a halogen atom, a lower alkyl
group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy
group, a lower alkylthio group, an amino group, a lower alkylamino group,
an amide of an amino group, an amide of a lower alkylamino group, a lower
alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an
amide of a carboxy group, a lower alkylsulfonyl group, a nitro group or a
cyano group;in the case where R1 is a lower alkyl group, a lower
alkoxy group, a lower alkylthio group, a lower alkylamino group, an amide
of a lower alkylamino group, a lower alkylcarbonyl group or a lower
alkylsulfonyl group, the lower alkyl group, lower alkoxy group, lower
alkylthio group, lower alkylamino group, amide of a lower alkylamino
group, lower alkylcarbonyl group or lower alkylsulfonyl group may have
one or a plurality of groups selected from a halogen atom, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group,
an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group
substituted with at least a halogen atom, a lower cycloalkyloxy group, an
aryloxy group, a heterocyclic oxy group, a lower alkylthio group, a lower
cycloalkylthio group, an arylthio group, a heterocyclic thio group, an
amino group, a lower alkylamino group, a lower cycloalkylamino group, an
arylamino group, a heterocyclic amino group, an amide of an amino group,
an amide of a lower alkylamino group, an amide of a lower cycloalkylamino
group, an amide of an arylamino group, an amide of a heterocyclic amino
group, a lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a carboxy group, an
ester of a carboxy group, an amide of a carboxy group, a lower
alkylsulfonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl
group, a heterocyclic sulfonyl group, a sulfonic acid group, an ester of
a sulfonic acid group, an amide of a sulfonic acid group, a nitro group
and a cyano group as substituents;p represents an integer of 0 to 3;in
the case where p is 2 or 3, each R1 may be the same or different;q
represents 0;R3 represents a hydrogen atom, a lower alkyl group, a
lower alkenyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl
group or an arylcarbonyl group;in the case where R3 is a lower alkyl
group, the lower alkyl group may have one or a plurality of aryl groups
as substituents;in the case where R3 is an arylcarbonyl group, the
arylcarbonyl group may have one or a plurality of groups selected from a
halogen atom and a lower alkyl group as substituents;R4 and R5
may be the same or different and represent a hydrogen atom, a halogen
atom, a lower alkyl group, a lower cycloalkyl group, aryl or a
heterocyclic group;in the case where R4 or R5 is a lower alkyl
group, the lower alkyl group may have one or a plurality of groups
selected from a halogen atom, a hydroxy group, an ester of a hydroxy
group, a lower alkoxy group, a lower alkoxy group substituted with at
least a halogen atom, a lower alkylthio group, an amino group, a lower
alkylamino group, an amide of an amino group, an amide of a lower
alkylamino group, a lower alkylcarbonyl group, a carboxy group, an ester
of a carboxy group, an amide of a carboxy group, a nitro group and a
cyano group as substituents;in the case where R4 or R5 is a
lower cycloalkyl group, aryl or a heterocyclic group, the lower
cycloalkyl group, aryl or heterocyclic group may have one or a plurality
of groups selected from a halogen atom, a lower alkyl group, a lower
alkyl group substituted with at least a halogen atom, a hydroxy group, an
ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group
substituted with at least a halogen atom, a lower alkylthio group, an
amino group, a lower alkylamino group, an amide of an amino group, an
amide of a lower alkylamino group, a lower alkylcarbonyl group, a carboxy
group, an ester of a carboxy group, an amide of a carboxy group, a lower
alkylsulfonyl group, a nitro group and a cyano group as
substituents;R4 and R5 may be combined together to form a 3- to
8-membered lower cycloalkane ring;R6 represents a hydrogen atom, a
lower alkyl group, a lower alkenyl group, a lower alkynyl group or a
lower cycloalkyl group;in the case where R6 is a lower alkyl group,
a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group,
the lower alkyl group, lower alkenyl group, lower alkynyl group or lower
cycloalkyl group may have one or a plurality of groups selected from a
halogen atom and an aryl group as substituents;A represents a lower
alkylene group;R7 represents OR8, NR8R9 or
SR8;R8 and R9 may be the same or different and represent a
hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower cycloalkyl group, an aryl group, a heterocyclic
group, a formyl group, a lower alkylcarbonyl group, a lower
alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower
cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl
group, a carboxy group, a lower alkoxycarbonyl group, a lower
alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, a lower
cycloalkyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclic
oxycarbonyl group, a lower alkylsulfonyl group, a lower alkenylsulfonyl
group, a lower alkynylsulfonyl group, a lower cycloalkylsulfonyl group,
an arylsulfonyl group, a heterocyclic sulfonyl group, an aminocarbonyl
group, a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl
group, a lower alkynylaminocarbonyl group, a lower
cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a
heterocyclic aminocarbonyl group;in the case where R8 or R9 is
a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkylcarbonyl group, a lower alkenylcarbonyl group, a lower
alkynylcarbonyl group, a lower alkoxycarbonyl group, a lower
alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, a lower
alkylsulfonyl group, a lower alkenylsulfonyl group, a lower
alkynylsulfonyl group, a lower alkylaminocarbonyl group, a lower
alkenylaminocarbonyl group or a lower alkynylaminocarbonyl group, the
lower alkyl group, lower alkenyl group, lower alkynyl group, lower
alkylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl
group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, lower
alkynyloxycarbonyl group, lower alkylsulfonyl group, lower
alkenylsulfonyl group, lower alkynylsulfonyl group, lower
alkylaminocarbonyl group, lower alkenylaminocarbonyl group or lower
alkynylaminocarbonyl group may have one or a plurality of groups selected
from a halogen atom, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower
alkoxy group, a lower alkoxy group substituted with at least a halogen
atom, a lower alkylthio group, an amino group, a lower alkylamino group,
an amide of an amino group, an amide of a lower alkylamino group, a lower
alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an
amide of a carboxy group, a lower alkylsulfonyl group, a nitro group and
a cyano group as substituents;in the case where R8 or R9 is a
lower cycloalkyl group, an aryl group, a heterocyclic group, a lower
cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl
group, a lower cycloalkyloxycarbonyl group, an aryloxycarbonyl group, a
heterocyclic oxycarbonyl group, a lower cycloalkylsulfonyl group, an
arylsulfonyl group, a heterocyclic sulfonyl group, a lower
cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a
heterocyclic aminocarbonyl group, the lower cycloalkyl group, aryl group,
heterocyclic group, lower cycloalkylcarbonyl group, arylcarbonyl group,
heterocyclic carbonyl group, lower cycloalkyloxycarbonyl group,
aryloxycarbonyl group, heterocyclic oxycarbonyl group, lower
cycloalkylsulfonyl group, arylsulfonyl group, heterocyclic sulfonyl
group, lower cycloalkylaminocarbonyl group, arylaminocarbonyl group or
heterocyclic aminocarbonyl group may have one or a plurality of groups
selected from a halogen atom, a lower alkyl group, a lower alkyl group
substituted with at least a halogen atom, a lower alkyl group substituted
with at least a hydroxy group, a lower alkenyl group, a lower alkynyl
group, a lower cycloalkyl group, an aryl group, a heterocyclic group, a
hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower
alkoxy group substituted with at least a halogen atom, a lower alkenyloxy
group, a lower alkynyloxy group, a lower alkylthio group, an amino group,
a lower alkylamino group, an amide of an amino group, an amide of a lower
alkylamino group, a lower alkylcarbonyl group, a carboxy group, an ester
of a carboxy group, an amide of a carboxy group, a lower alkylsulfonyl
group, a nitro group and a cyano group as substituents;in the case where
R7 is NR8R9, R8 and R9 may be combined together
to form a 5- or 6-membered nitrogen-containing heterocyclic ring; andX
represents O.

4. The compound or a salt thereof according to claim 1, wherein in the
general formula (1), R1 represents a halogen atom, a lower alkyl
group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy
group, a lower alkylthio group, an amino group, an amide of an amino
group, an amide of a lower alkylamino group, a lower alkylcarbonyl group,
a carboxy group, an ester of a carboxy group, a nitro group or a cyano
group;in the case where R1 is a lower alkyl group or a lower alkoxy
group, the lower alkyl group or lower alkoxy group may have one or a
plurality of groups selected from a halogen atom, a hydroxy group and a
lower alkoxy group as substituents;p represents 1, 2 or 3;in the case
where p is 2 or 3, each R1 may be the same or different;q represents
0;R3 represents a hydrogen atom;R4 and R5 may be the same
or different and represent a lower alkyl group;R6 represents a
hydrogen atom, a lower alkyl group or a lower alkenyl group;A represents
a lower alkylene group;R7 represents OR8 or
NR8R9;R8 and R9 may be the same or different and
represent a hydrogen atom, an aryl group, an arylcarbonyl group or a
heterocyclic carbonyl group;in the case where R8 or R9 is an
aryl group, an arylcarbonyl group or a heterocyclic carbonyl group, the
aryl group, arylcarbonyl group or heterocyclic carbonyl group may have
one or a plurality of groups selected from a halogen atom, a lower alkyl
group, a lower alkyl group substituted with at least a halogen atom, a
lower alkyl group substituted with at least a hydroxy group, a lower
alkenyl group, an aryl group, a lower alkoxy group, a lower alkylcarbonyl
group, an ester of a carboxy group, a nitro group and a cyano group as
substituents; andX represents O.

5. The compound or a salt thereof according to claim 1, wherein in the
general formula (1), R1 represents a halogen atom, a hydroxy group,
an ester of a hydroxy group, a lower alkoxy group, an amide of an amino
group or an amide of a lower alkylamino group;p represents 2 or 3, in
this case, each R1 may be the same or different;q represents
0;R3 represents a hydrogen atom;R4 and R5 may be the same
or different and represent a lower alkyl group;R6 represents a lower
alkyl group;A represents a lower alkylene group;R7 represents
OR8 or NR8R9;R8 represents an aryl group, an
arylcarbonyl group or a heterocyclic carbonyl group, in this case, the
aryl group, arylcarbonyl group or heterocyclic carbonyl group may have
one or a plurality of groups selected from a halogen atom, a lower alkyl
group, a lower alkyl group substituted with at least a halogen atom, a
lower alkyl group substituted with at least a hydroxy group, a lower
alkenyl group, an aryl group, a lower alkoxy group, a lower alkylcarbonyl
group, an ester of a carboxy group, a nitro group and a cyano group as
substituents;R9 represents a hydrogen atom; andX represents O.

6. The compound or a salt thereof according to any one of claims 1 to 4,
wherein in the general formula (1), R1 represents a halogen atom, a
hydroxy group, an ester of a hydroxy group, a lower alkoxy group, an
amide of an amino group or an amide of a lower alkylamino group.

7. The compound or a salt thereof according to any one of claims 1 to 5,
wherein in the general formula (1), R4, R5 and R6 each
represent a methyl group.

8. The compound or a salt thereof according to any one of claims 1 to 5,
wherein in the general formula (1), R8 represents an aryl group, an
arylcarbonyl group or a heterocyclic carbonyl group, and the aryl group
represents a phenyl group, the arylcarbonyl group represents a
phenylcarbonyl group, and the heterocyclic carbonyl group represents a
thiophenecarbonyl group.

9. The compound or a salt thereof according to any one of claims 1 to 5,
wherein in the general formula (1), A represents a methylene group.

10. The compound or a salt thereof according to any one of claims 1 to 5,
wherein in R1 in the general formula (1), the ester of a hydroxy
group represents --OCO--Ra1, in which the Ra1 represents a
hydrogen atom, a lower alkyl group which may have at least a substituent,
a lower alkenyl group which may have at least a substituent, a lower
alkynyl group which may have at least a substituent, a lower cycloalkyl
group which may have at least a substituent, an aryl group which may have
at least a substituent, a heterocyclic group which may have at least a
substituent, a lower alkoxy group which may have at least a substituent,
a lower alkenyloxy group which may have at least a substituent, a lower
alkynyloxy group which may have at least a substituent, a lower
cycloalkyloxy group which may have at least a substituent, an aryloxy
group which may have at least a substituent, a heterocyclic oxy group
which may have at least a substituent, an amino group, a lower alkylamino
group which may have at least a substituent, a lower cycloalkylamino
group which may have at least a substituent, an arylamino group which may
have at least a substituent or a heterocyclic amino group which may have
at least a substituent.

11. The compound or a salt thereof according to claim 10, wherein in
R1 in the general formula (1), the ester of a hydroxy group
represents --OCO--Ra1, in which the Ra1 represents a hydrogen
atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl
group, an aryl group, a heterocyclic group, a lower alkoxy group, a lower
alkenyloxy group, a lower cycloalkyloxy group, an aryloxy group, a
heterocyclic oxy group, an amino group, a lower alkylamino group, a lower
cycloalkylamino group, an arylamino group or a heterocyclic amino
group;in the case where Ra1 is a lower alkyl group, a lower alkenyl
group, a lower alkoxy group, a lower alkenyloxy group or a lower
alkylamino group, the lower alkyl group, lower alkenyl group, lower
alkoxy group, lower alkenyloxy group or lower alkylamino group may have
one or a plurality of groups selected from a halogen atom, an aryl group,
a heterocyclic group, a hydroxy group, an ester of a hydroxy group, an
amino group, a lower alkylamino group, a carboxy group and an ester of a
carboxy group as substituents; andin the case where Ra1 is a lower
cycloalkyl group, an aryl group, a heterocyclic group, a lower
cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a lower
cycloalkylamino group, an arylamino group or a heterocyclic amino group,
the lower cycloalkyl group, aryl group, heterocyclic group, lower
cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower
cycloalkylamino group, arylamino group or heterocyclic amino group may
have one or a plurality of groups selected from a halogen atom, a lower
alkyl group, a lower alkyl group substituted with at least a halogen
atom, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group,
a mercapto group, a lower alkylthio group, a formyl group, a lower
alkylcarbonyl group, a carboxy group, an ester of a carboxy group, a
nitro group and a cyano group as substituents.

12. The compound or a salt thereof according to claim 10, wherein in
R1 in the general formula (1), the ester of a hydroxy group
represents --OCO--Ra, in which the Ra1 represents a lower alkyl
group, a lower alkenyl group, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a lower alkoxy group, an aryloxy group, a lower
alkylamino group, a lower cycloalkylamino group, an arylamino group or a
heterocyclic amino group;in the case where Ra1 is a lower alkyl
group, the lower alkyl group may have one or a plurality of groups
selected from an aryl group and a lower alkylamino group as
substituents;in the case where Ra1 is an aryl group, the aryl group
may have one or a plurality of groups selected from a halogen atom, a
lower alkyl group, a lower alkyl group substituted with at least a
halogen atom, an ester of a hydroxy group, a lower alkoxy group, a lower
alkylthio group, a lower alkylcarbonyl group, an ester of a carboxy group
and a nitro group as substituents;in the case where Ra1 is a
heterocyclic group, the heterocyclic group may have one or a plurality of
groups selected from a halogen atom, a lower alkyl group, a hydroxy group
and a lower alkoxy group as substituents;in the case where Ra1 is a
lower alkylamino group, the lower alkylamino group may have one or a
plurality of groups selected from an aryl group, a heterocyclic group and
an ester of a carboxy group as substituents; andin the case where
Ra1 is an arylamino group, the arylamino group may have one or a
plurality of groups selected from a halogen atom, a lower alkyl group and
a lower alkoxy group as substituents.

13. The compound or a salt thereof according to any one of claims 1 to 5,
wherein in R1 in the general formula (1), the amide of an amino
group represents --NHCO--Rb1, in which the Rb1 represents a
hydrogen atom, a lower alkyl group which may have at least a substituent,
a lower alkenyl group which may have at least a substituent, a lower
alkynyl group which may have at least a substituent, a lower cycloalkyl
group which may have at least a substituent, an aryl group which may have
at least a substituent, a heterocyclic group which may have at least a
substituent, a lower alkoxy group which may have at least a substituent,
a lower alkenyloxy group which may have at least a substituent, a lower
alkynyloxy group which may have at least a substituent, a lower
cycloalkyloxy group which may have at least a substituent, an aryloxy
group which may have at least a substituent, a heterocyclic oxy group
which may have at least a substituent, an amino group, a lower alkylamino
group which may have at least a substituent, a lower cycloalkylamino
group which may have at least a substituent, an arylamino group which may
have at least a substituent or a heterocyclic amino group which may have
at least a substituent.

14. The compound or a salt thereof according to claim 13, wherein in
R1 in the general formula (1), the amide of an amino group
represents --NHCO--Rb1, in which the Rb1 represents a hydrogen
atom, a lower alkyl group, a lower alkenyl group, a lower cycloalkyl
group, an aryl group, a heterocyclic group, a lower alkoxy group, a lower
alkenyloxy group, a lower cycloalkyloxy group, an aryloxy group, a
heterocyclic oxy group, an amino group, a lower alkylamino group, a lower
cycloalkylamino group, an arylamino group or a heterocyclic amino
group;in the case where Rb1 is a lower alkyl group, a lower alkenyl
group, a lower alkoxy group, a lower alkenyloxy group or a lower
alkylamino group, the lower alkyl group, lower alkenyl group, lower
alkoxy group, lower alkenyloxy group or lower alkylamino group may have
one or a plurality of groups selected from a halogen atom, an aryl group,
a heterocyclic group, a hydroxy group, an ester of a hydroxy group, an
amino group, a lower alkylamino group, a carboxy group and an ester of a
carboxy group as substituents; andin the case where Rb1 is a lower
cycloalkyl group, an aryl group, a heterocyclic group, a lower
cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a lower
cycloalkylamino group, an arylamino group or a heterocyclic amino group,
the lower cycloalkyl group, aryl group, heterocyclic group, lower
cycloalkyloxy group, aryloxy group, heterocyclic oxy group, lower
cycloalkylamino group, arylamino group or heterocyclic amino group may
have one or a plurality of groups selected from a halogen atom, a lower
alkyl group, a lower alkyl group substituted with at least a halogen
atom, a hydroxy group, an ester of a hydroxy group, a lower alkoxy group,
a mercapto group, a lower alkylthio group, a formyl group, a lower
alkylcarbonyl group, a carboxy group, an ester of a carboxy group, a
nitro group and a cyano group as substituents.

15. The compound or a salt thereof according to claim 13, wherein in
R1 in the general formula (1), the amide of an amino group
represents --NHCO--Rb1, in which the Rb1 represents a lower
alkyl group, an aryl group, a heterocyclic group, an aryloxy group, a
lower alkylamino group or an arylamino group;in the case where Rb1
is a lower alkyl group, the lower alkyl group may have one or a plurality
of amino groups as substituents;in the case where Rb1 is an aryl
group, the aryl group may have one or a plurality of groups selected from
a halogen atom, a lower alkyl group, a lower alkyl group substituted with
at least a halogen atom, an ester of a hydroxy group, a lower alkoxy
group, a lower alkylthio group, a lower alkylcarbonyl group, an ester of
a carboxy group and a nitro group as substituents;in the case where
Rb1 is a heterocyclic group, the heterocyclic group may have one or
a plurality of groups selected from a halogen atom, a lower alkyl group,
a hydroxy group and a lower alkoxy group as substituents; andin the case
where Rb1 is a lower alkylamino group, the lower alkylamino group
may have one or a plurality of aryl groups as substituents.

16. The compound or a salt thereof according to any one of claims 1 to 5,
wherein in R1 in the general formula (1), the amide of a lower
alkylamino group represents --NRc1CO--Rc2, in which the
Rc1 represents a lower alkyl group which may have at least a
substituent, and the Rc2 represents a hydrogen atom, a lower alkyl
group which may have at least a substituent, a lower alkenyl group which
may have at least a substituent, a lower alkynyl group which may have at
least a substituent, a lower cycloalkyl group which may have at least a
substituent, an aryl group which may have at least a substituent, a
heterocyclic group which may have at least a substituent, a lower alkoxy
group which may have at least a substituent, a lower alkenyloxy group
which may have at least a substituent, a lower alkynyloxy group which may
have at least a substituent, a lower cycloalkyloxy group which may have
at least a substituent, an aryloxy group which may have at least a
substituent, a heterocyclic oxy group which may have at least a
substituent, an amino group, a lower alkylamino group which may have at
least a substituent, a lower cycloalkylamino group which may have at
least a substituent, an arylamino group which may have at least a
substituent or a heterocyclic amino group which may have at least a
substituent.

17. The compound or a salt thereof according to claim 16, wherein in
R1 in the general formula (1), the amide of a lower alkylamino group
represents --NRc1CO--Rc2, in which the Rc1 represents a
lower alkyl group, and the Rc2 represents a hydrogen atom, a lower
alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower alkoxy group, a lower alkenyloxy
group, a lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy
group, an amino group, a lower alkylamino group, a lower cycloalkylamino
group, an arylamino group or a heterocyclic amino group;in the case where
Rc2 is a lower alkyl group, a lower alkenyl group, a lower alkoxy
group, a lower alkenyloxy group or a lower alkylamino group, the lower
alkyl group, lower alkenyl group, lower alkoxy group, lower alkenyloxy
group or lower alkylamino group may have one or a plurality of groups
selected from a halogen atom, an aryl group, a heterocyclic group, a
hydroxy group, an ester of a hydroxy group, an amino group, a lower
alkylamino group, a carboxy group and an ester of a carboxy group as
substituents; andin the case where Rc2 is a lower cycloalkyl group,
an aryl group, a heterocyclic group, a lower cycloalkyloxy group, an
aryloxy group, a heterocyclic oxy group, a lower cycloalkylamino group,
an arylamino group or a heterocyclic amino group, the lower cycloalkyl
group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy
group, heterocyclic oxy group, lower cycloalkylamino group, arylamino
group or heterocyclic amino group may have one or a plurality of groups
selected from a halogen atom, a lower alkyl group, a lower alkyl group
substituted with at least a halogen atom, a hydroxy group, an ester of a
hydroxy group, a lower alkoxy group, a mercapto group, a lower alkylthio
group, a formyl group, a lower alkylcarbonyl group, a carboxy group, an
ester of a carboxy group, a nitro group and a cyano group as
substituents.

18. The compound or a salt thereof according to claim 16, wherein in
R1 in the general formula (1), the amide of a lower alkylamino group
represents --NRc1CO--Rc2, in which the Rc1 represents a
lower alkyl group, and the Rc2 represents a lower alkyl group, an
aryl group or a heterocyclic group;in the case where Rc2 is a lower
alkyl group, the lower alkyl group may have one or a plurality of amino
groups as substituents;in the case where Rc2 is an aryl group, the
aryl group may have one or a plurality of groups selected from a
halogen-atom, a lower alkyl group, a lower alkyl group substituted with
at least a halogen atom, an ester of a hydroxy group, a lower alkoxy
group, a lower alkylthio group, a lower alkylcarbonyl group, an ester of
a carboxy group and a nitro group as substituents;in the case where
Rc2 is a heterocyclic group, the heterocyclic group may have one or
a plurality of groups selected from a halogen atom, a lower alkyl group,
a hydroxy group and a lower alkoxy group as substituents; andin the case
where Rc2 is a lower alkylamino group, the lower alkylamino group
may have one or a plurality of aryl groups as substituents.

20. A pharmaceutical composition, comprising the compound or a salt
thereof according to any one of claims 1 to 5.

21. A modulator of glucocorticoid receptor, comprising the compound or a
salt thereof according to any one of claims 1 to 5 as an active
ingredient.

22. A method of preventing or treating a glucocorticoid receptor-related
disease, comprising administering a therapeutically effective amount of
the compound or a salt thereof according to any one of claims 1 to 5 to a
patient.

23. The prevention or treatment method according to claim 22, wherein the
glucocorticoid receptor-related disease is a metabolic disorder, an
inflammatory disease, an autoimmune disease, an allergic disease, a
central nervous system disease, a cardiovascular disease, a
homeostasis-related disease or glaucoma.

Description:

TECHNICAL FIELD

[0001]The present invention relates to a novel
1,2,3,4-tetrahydroquinoxaline derivative or a salt thereof, which is
useful as a pharmaceutical. The derivative has a glucocorticoid receptor
binding activity and is useful as a glucocorticoid receptor modulator
having a nonsteroidal structure (a glucocorticoid receptor agonist and/or
a glucocorticoid receptor antagonist).

BACKGROUND ART

[0002]A glucocorticoid receptor is a 94 kDa ligand-activated intracellular
transcriptional factor that is a member of the nuclear receptor
superfamily. This receptor is a mediator of glucocorticoid action which
effects the metabolism of carbohydrates, proteins, fats and the like, the
suppression of the immune or inflammatory responses, the activatation of
the central nervous system, the regulation of the cardiovascular function
and the basal and stress-related homeostasis and the like. As
glucocorticoid action-related diseases, metabolic disorders such as
diabetes and obesity, inflammatory diseases such as arthritis, enteritis
and chronic obstructive pulmonary diseases, autoimmune diseases such as
connective tissue diseases, allergic diseases such as asthma, atopic
dermatitis, allergic rhinitis and conjunctivitis, central nervous system
diseases such as psychiatric disorders, Alzheimer's disease and drug use
disorders, cardiovascular diseases such as hypertension, hypercalcemia,
hyperinsulinemia and hyperlipidemia, homeostasis-related diseases causing
an abnormality of neuro-immune-endocrine balance, glaucoma and the like
are known. (SOUGOU RINSYOU, 54(7), 1951-2076 (2005), JP-A-2002-193955.)

[0003]Therefore, a compound having a glucocorticoid receptor binding
activity is considered to be useful as a preventive and/or therapeutic
agent for these diseases.

[0004]As such a compound having a glucocorticoid receptor binding
activity, glucocorticoid receptor agonists synthesized in the living body
such as cortisol and corticosterone, synthetic glucocorticoid receptor
agonists such as dexamethasone, prednisone and prednisilone,
non-selective glucocorticoid receptor antagonists such as RU486 and the
like are known. (JP-A-2002-193955)

[0005]On the other hand, compounds having a 1,2,3,4-tetrahydroquinoxaline
structure are disclosed in WO 04/099192 and JP-A-5-148243 and the like.
The compounds disclosed in WO 04/099192 are protein thyrosine phosphatase
inhibitors essentially having a carboxylic group. On the other hand, a
large number of compounds having 1,2,3,4-tetrahydroquinoxaline structure
are disclosed as anti-virus agents in JP-A-5-148243. However, the present
compound has not been specifically disclosed in any of patents.

DISCLOSURE OF THE INVENTION

Problems to be Solved

[0006]It is a very interesting subject to study synthesis of a novel
1,2,3,4-tetrahydroquinoxaline derivative and to find a pharmacological
action of the derivative.

Means of Solving Problems

[0007]The present inventors conducted studies about the synthesis of
1,2,3,4-tetrahydroquinoxaline derivatives having a novel chemical
structure, and succeeded in producing a large number of novel compounds.
Further, the present inventors studied the pharmacological actions of the
derivatives and as a result, they found that the derivatives have a
glucocorticoid receptor binding activity and are useful as a
pharmaceutical, and thus the present invention has been completed.

[0008]That is, the present invention relates to a compound represented by
the following general formula (1) or a salt thereof (hereinafter referred
to as "the present compound") and a pharmaceutical composition containing
the same. Further, a preferred invention in its pharmaceutical use
relates to a glucocorticoid receptor modulator, and its target diseases
are glucocorticoid receptor-related diseases, that is, metabolic
disorders such as diabetes and obesity, inflammatory diseases such as
arthritis, enteritis and chronic obstructive pulmonary diseases,
autoimmune diseases such as connective tissue diseases, allergic diseases
such as asthma, atopic dermatitis, allergic rhinitis and conjunctivitis,
central nervous system diseases such as psychiatric disorders,
Alzheimer's disease and drug use disorders, cardiovascular diseases such
as hypertension, hypercalcemia, hyperinsulinemia and hyperlipidemia,
homeostasis-related diseases causing an abnormality of
neuro-immune-endocrine balance, glaucoma and the like. A particularly
preferred invention is an invention relating to a preventive or a
therapeutic agent for these diseases.

##STR00002##

[wherein R1 represents a halogen atom, a lower alkyl group which may
have at least a substituent, a lower cycloalkyl group which may have at
least a substituent, an aryl group which may have at least a substituent,
a heterocyclic group which may have at least a substituent, a hydroxy
group, an ester of a hydroxy group, a lower alkoxy group which may have
at least a substituent, a lower cycloalkyloxy group which may have at
least a substituent, an aryloxy group which may have at least a
substituent, a heterocyclic oxy group which may have at least a
substituent, a mercapto group, an ester of a mercapto group, a lower
alkylthio group which may have at least a substituent, a lower
cycloalkylthio group which may have at least a substituent, an arylthio
group which may have at least a substituent, a heterocyclic thio group
which may have at least a substituent, an amino group, a lower alkylamino
group which may have at least a substituent, a lower cycloalkylamino
group which may have at least a substituent, an arylamino group which may
have at least a substituent, a heterocyclic amino group which may have at
least a substituent, an amide of an amino group, an amide of a lower
alkylamino group which may have at least a substituent, an amide of a
lower cycloalkylamino group which may have at least a substituent, an
amide of an arylamino group which may have at least a substituent, an
amide of a heterocyclic amino group which may have at least a
substituent, a formyl group, a lower alkylcarbonyl group which may have
at least a substituent, a lower cycloalkylcarbonyl group which may have
at least a substituent, an arylcarbonyl group which may have at least a
substituent, a heterocyclic carbonyl group which may have at least a
substituent, a carboxy group, an ester of a carboxy group, an amide of a
carboxy group, a lower alkylsulfonyl group which may have at least a
substituent, a lower cycloalkylsulfonyl group which may have at least a
substituent, an arylsulfonyl group which may have at least a substituent,
a heterocyclic sulfonyl group which may have at least a substituent, a
sulfonic acid group, an ester of a sulfonic acid group, an amide of a
sulfonic acid group, a nitro group or a cyano group;

[0009]p represents an integer of 0 to 5;

[0010]in the case where p is 2 to 5, each R1 may be the same or
different;

[0011]R2 represents a halogen atom, a lower alkyl group which may
have at least a substituent, a hydroxy group, an ester of a hydroxy group
or a lower alkoxy group which may have at least a substituent;

[0012]q represents an integer of 0 to 2;

[0013]in the case where q is 2, each R2 may be the same or different;

[0014]R3 represents a hydrogen atom, a lower alkyl group which may
have at least a substituent, a lower alkenyl group which may have at
least a substituent, a lower alkylcarbonyl group which may have at least
a substituent, a lower alkenylcarbonyl group which may have at least a
substituent or an arylcarbonyl group which may have at least a
substituent;

[0015]R4 and R5 may be the same or different and represent a
hydrogen atom, a halogen atom, a lower alkyl group which may have at
least a substituent, a lower alkenyl group which may have at least a
substituent, a lower alkynyl group which may have at least a substituent,
a lower cycloalkyl group which may have at least a substituent, an aryl
group which may have at least a substituent or a heterocyclic group which
may have at least a substituent;

[0016]R4 and R5 may be combined together to form a 3- to
8-membered lower cycloalkane ring which may have at least a substituent;

[0017]R6 represents a hydrogen atom, a lower alkyl group which may
have at least a substituent, a lower alkenyl group which may have at
least a substituent, a lower alkynyl group which may have at least a
substituent, a lower cycloalkyl group which may have at least a
substituent, an aryl group which may have at least a substituent or a
heterocyclic group which may have at least a substituent;

[0018]A represents a lower alkylene group which may have at least a
substituent;

[0019]R7 represents OR8, NR8R9, SR8, S(O)R8
or S(O)2R8;

[0020]R8 and R9 may be the same or different and represent a
hydrogen atom, a lower alkyl group which may have at least a substituent,
a lower alkenyl group which may have at least a substituent, a lower
alkynyl group which may have at least a substituent, a lower cycloalkyl
group which may have at least a substituent, an aryl group which may have
at least a substituent, a heterocyclic group which may have at least a
substituent, a formyl group, a lower alkylcarbonyl group which may have
at least a substituent, a lower alkenylcarbonyl group which may have at
least a substituent, a lower alkynylcarbonyl group which may have at
least a substituent, a lower cycloalkylcarbonyl group which may have at
least a substituent, an arylcarbonyl group which may have at least a
substituent, a heterocyclic carbonyl group which may have at least a
substituent, a carboxy group, a lower alkoxycarbonyl group which may have
at least a substituent, a lower alkenyloxycarbonyl group which may have
at least a substituent, a lower alkynyloxycarbonyl group which may have
at least a substituent, a lower cycloalkyloxycarbonyl group which may
have at least a substituent, an aryloxycarbonyl group which may have at
least a substituent, a heterocyclic oxycarbonyl group which may have at
least a substituent, a lower alkylsulfonyl group which may have at least
a substituent, a lower alkenylsulfonyl group which may have at least a
substituent, a lower alkynylsulfonyl group which may have at least a
substituent, a lower cycloalkylsulfonyl group which may have at least a
substituent, an arylsulfonyl group which may have at least a substituent,
a heterocyclic sulfonyl group which may have at least a substituent, an
aminocarbonyl group, a lower alkylaminocarbonyl group which may have at
least a substituent, a lower alkenylaminocarbonyl group which may have at
least a substituent, a lower alkynylaminocarbonyl group which may have at
least a substituent, a lower cycloalkylaminocarbonyl group which may have
at least a substituent, an arylaminocarbonyl group which may have at
least a substituent or a heterocyclic aminocarbonyl group which may have
at least a substituent;

[0021]in the case where R7 is NR8R9, R8 and R9
may be combined together to form a 3- to 8-membered nitrogen-containing
heterocyclic ring which may have at least a substituent; and

[0022]X represents O or S. Hereinafter the same shall apply.]

ADVANTAGE OF THE INVENTION

[0023]The present invention provides a 1,2,3,4-tetrahydroquinoxaline
derivative or a salt thereof, which is useful as a pharmaceutical. The
present compound has an excellent glucocorticoid receptor binding
activity and is useful as a glucocorticoid receptor modulator. In
particular, the present compound is useful as a preventive or therapeutic
agent for glucocorticoid action related diseases, that is, metabolic
disorders such as diabetes and obesity, inflammatory diseases such as
arthritis, enteritis and chronic obstructive pulmonary diseases,
autoimmune diseases such as connective tissue diseases, allergic diseases
such as asthma, atopic dermatitis, allergic rhinitis and conjunctivitis,
central nervous system diseases such as psychiatric disorders,
Alzheimer's disease and drug use disorders, cardiovascular diseases such
as hypertension, hypercalcemia, hyperinsulinemia and hyperlipidemia,
homeostasis-related diseases causing an abnormality of
neuro-immune-endocrine balance, glaucoma and the like.

BEST MODE FOR CARRYING OUT THE INVENTION

[0024]Hereinafter, definitions of terms and phrases (atoms, groups, rings
and the like) to be used in this specification will be described in
detail.

[0031]The "aryl group" refers to a residue formed by removing one hydrogen
atom from a monocyclic aromatic hydrocarbon group, or bicyclic or
tricyclic condensed polycyclic aromatic hydrocarbon having 6 to 14 carbon
atoms. Further, A residue formed by removing one hydrogen atom from
bicyclic or tricyclic condensed polycyclic hydrocarbon having 6 to 14
carbon atoms is also included in the scope of the "aryl group". Specific
examples thereof include phenyl, naphthyl, anthryl, phenanthryl and
fluorenyl groups and the like.

[0032]The "heterocyclic group" refers to a residue formed by removing one
hydrogen atom from a saturated or unsaturated monocyclic heterocyclic
ring, or a bicyclic or tricyclic condensed polycyclic heterocyclic ring
having one or a plurality of heteroatoms selected from a nitrogen atom,
an oxygen atom and a sulfur atom in the ring.

[0033]Specific examples of the saturated monocyclic heterocyclic ring
include pyrrolidine, pyrazolidine, imidazolidine, triazolidine,
piperidine, hexahydropyridazine, hexahydropyrimidine, piperazine,
homopiperidine and homopiperazine rings and the like having a nitrogen
atom in the ring, tetrahydrofuran and tetrahydropyran rings and the like
having an oxygen atom in the ring, tetrahydrothiophene and
tetrahydrothiopyran rings and the like having a sulfur atom in the ring,
oxazolidine, isoxazolidine and morpholine rings and the like having a
nitrogen atom and an oxygen atom in the ring, and thiazolidine,
isothiazolidine and thiomorpholine rings and the like having a nitrogen
atom and a sulfur atom in the ring.

[0034]Further, such a saturated monocyclic heterocyclic ring can be
condensed with a benzene ring or the like to form a bicyclic or tricyclic
condensed polycyclic heterocyclic ring such as a dihydroindole,
dihydroindazole, dihydrobenzimidazole, tetrahydroquinoline,
tetrahydroisoquinoline, tetrahydrocinnoline, tetrahydrophthalazine,
tetrahydroquinazoline, tetrahydroquinoxaline, dihydrobenzofuran,
dihydroisobenzofuran, chromane, isochromane, dihydrobenzothiophene,
dihydroisobenzothiophene, thiochromane, isothiochromane,
dihydrobenzoxazole, dihydrobenzisoxazole, dihydrobenzoxazine,
dihydrobenzothiazole, dihydrobenzisothiazole, dihydrobenzothiazine,
xanthene, 4a-carbazole and perimidine rings and the like.

[0035]Specific examples of the unsaturated monocyclic heterocyclic ring
include dihydropyrrole, pyrrole, dihydropyrazole, pyrazole,
dihydroimidazole, imidazole, dihydrotriazole, triazole,
tetrahydropyridine, dihydropyridine, pyridine, tetrahydropyridazine,
dihydropyridazine, pyridazine, tetrahydropyrimidine, dihydropyrimidine,
pyrimidine, tetrahydropyrazine, dihydropyrazine and pyrazine rings and
the like having a nitrogen atom in the ring, dihydrofuran, furan,
dihydropyran and pyran rings and the like having an oxygen atom in the
ring, dihydrothiophene, thiophene, dihydrothiopyran and thiopyran rings
and the like having a sulfur atom in the ring, dihydrooxazole, oxazole,
dihydroisoxazole, isoxazole, dihydrooxazine and oxazine rings and the
like having a nitrogen atom and an oxygen atom in the ring,
dihydrothiazole, thiazole, dihydroisothiazole, isothiazole,
dihydrothiazine and thiazine rings and the like having a nitrogen atom
and a sulfur atom in the ring.

[0037]The "lower alkoxy group" refers to a group formed by replacing the
hydrogen atom of a hydroxy group with a lower alkyl group. Specific
examples thereof include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy,
n-hexyloxy, n-heptyloxy, n-octyloxy, isopropoxy, isobutoxy, sec-butoxy,
tert-butoxy and isopentoxy groups and the like.

[0038]The "lower alkenyloxy group" refers to a group formed by replacing
the hydrogen atom of a hydroxy group with a lower alkenyl group. Specific
examples thereof include vinyloxy, propenyloxy, butenyloxy, pentenyloxy,
hexenyloxy, heptenyloxy, octenyloxy, isopropenyloxy,
2-methyl-1-propenyloxy and 2-methyl-2-butenyloxy groups and the like.

[0039]The "lower alkynyloxy group" refers to a group formed by replacing
the hydrogen atom of a hydroxy group with a lower alkynyl group. Specific
examples thereof include ethynyloxy, propynyloxy, butynyloxy,
pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, isobutynyloxy and
isopentynyloxy groups and the like.

[0040]The "lower cycloalkyloxy group" refers to a group formed by
replacing the hydrogen atom of a hydroxy group with a lower cycloalkyl
group. Specific examples thereof include cyclopropyloxy, cyclobutyloxy,
cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy groups.

[0041]The "aryloxy group" refers to a group formed by replacing the
hydrogen atom of a hydroxy group with an aryl group. Specific examples
thereof include phenoxy, naphthoxy, anthryloxy and phenanthryloxy groups
and the like.

[0042]The "heterocyclic oxy group" refers to a group formed by replacing
the hydrogen atom of a hydroxy group with a heterocyclic group.

[0043]The "lower alkylthio group" refers to a group formed by replacing
the hydrogen atom of a mercapto group with a lower alkyl group. Specific
examples thereof include methylthio, ethylthio, n-propylthio,
n-butylthio, n-pentylthio, n-hexylthio, n-heptylthio, n-octylthio,
isopropylthio, isobutylthio, sec-butylthio, tert-butylthio and
isopentylthio groups and the like.

[0044]The "lower cycloalkylthio group" refers to a group formed by
replacing the hydrogen atom of a mercapto group with a lower cycloalkyl
group. Specific examples thereof include cyclopropylthio, cyclobutylthio,
cyclopentylthio, cyclohexylthio, cycloheptylthio and cyclooctylthio
groups.

[0045]The "arylthio group" refers to a group formed by replacing the
hydrogen atom of a mercapto group with an aryl group. Specific examples
thereof include phenylthio, naphthylthio, anthrylthio and phenanthrylthio
groups and the like.

[0046]The "heterocyclic thio group" refers to a group formed by replacing
the hydrogen atom of a mercapto group with a heterocyclic group.

[0047]The "lower alkylamino group" refers to a group formed by replacing
one or both of the hydrogen atoms of an amino group with a lower alkyl
group. Specific examples thereof include methylamino, ethylamino,
propylamino, dimethylamino, diethylamino and ethyl(methyl)amino groups
and the like.

[0048]The "lower cycloalkylamino group" refers to a group formed by
replacing one or both of the hydrogen atoms of an amino group with a
lower cycloalkyl group, or a group formed by replacing one of the
hydrogen atoms of an amino group with a lower cycloalkyl group and the
other hydrogen atom with a lower alkyl group, a lower alkenyl group or a
lower alkynyl group. Specific examples thereof include cyclopropylamino,
cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino,
cyclooctylamino, dicyclohexylamino, cyclohexyl(methyl)amino,
cyclohexyl(vinyl)amino and cyclohexyl(ethynyl)amino groups and the like.

[0049]The "arylamino group" refers to a group formed by replacing one or
both of the hydrogen atoms of an amino group with an aryl group, or a
group formed by replacing one of the hydrogen atoms of an amino group
with an aryl group and the other hydrogen atom with a lower alkyl group,
a lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group.
Specific examples thereof include phenylamino, naphthylamino,
anthrylamino, phenanthrylamino, diphenylamino, methyl(phenyl)amino,
ethyl(phenyl)amino, phenyl(vinyl)amino, ethynyl(phenyl)amino and
cyclohexyl(phenyl)amino groups and the like.

[0050]The "heterocyclic amino group" refers to a group formed by replacing
one or both of the hydrogen atoms of an amino group with a heterocyclic
group, or a group formed by replacing one of the hydrogen atoms of an
amino group with a heterocyclic group and the other hydrogen atom with a
lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower
cycloalkyl group or an aryl group.

[0051]The "lower alkylcarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkyl group.
Specific examples thereof include methylcarbonyl, ethylcarbonyl,
n-propylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl, n-hexylcarbonyl,
n-heptylcarbonyl, n-octylcarbonyl, isopropylcarbonyl, isobutylcarbonyl,
sec-butylcarbonyl, tert-butylcarbonyl and isopentylcarbonyl groups and
the like.

[0052]The "lower alkenylcarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkenyl group.
Specific examples thereof include vinylcarbonyl, propenylcarbonyl,
butenylcarbonyl, pentenylcarbonyl, hexenylcarbonyl, heptenylcarbonyl,
octenylcarbonyl, isopropenylcarbonyl, 2-methyl-1-propenylcarbonyl and
2-methyl-2-butenylcarbonyl groups and the like.

[0053]The "lower alkynylcarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkynyl group.
Specific examples thereof include ethynylcarbonyl, propynylcarbonyl,
butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl, heptynylcarbonyl,
octynylcarbonyl, isobutynylcarbonyl and isopentynylcarbonyl groups and
the like.

[0054]The "lower cycloalkylcarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower cycloalkyl
group. Specific examples thereof include cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
cycloheptylcarbonyl and cyclooctylcarbonyl groups.

[0055]The "arylcarbonyl group" refers to a group formed by replacing the
hydrogen atom of a formyl group with an aryl group. Specific examples
thereof include phenylcarbonyl, naphthylcarbonyl, anthrylcarbonyl and
phenanthrylcarbonyl groups and the like.

[0056]The "heterocyclic carbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a heterocyclic group.

[0057]The "lower alkoxycarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkoxy group.
Specific examples thereof include methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, n-butoxycarbonyl, n-pentoxycarbonyl,
n-hexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl,
isopropoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,
tert-butoxycarbonyl and isopentoxycarbonyl groups and the like.

[0058]The "lower alkenyloxycarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkenyloxy
group. Specific examples thereof include vinyloxycarbonyl,
propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl,
hexenyloxycarbonyl, heptenyloxycarbonyl, octenyloxycarbonyl,
isopropenyloxycarbonyl, 2-methyl-1-propenyloxycarbonyl and
2-methyl-2-butenyloxycarbonyl groups and the like.

[0059]The "lower alkynyloxycarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkynyloxy
group. Specific examples thereof include ethynyloxycarbonyl,
propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl,
hexynyloxycarbonyl, heptynyloxycarbonyl, octynyloxycarbonyl,
isobutynyloxycarbonyl and isopentynyloxycarbonyl groups and the like.

[0060]The "lower cycloalkyloxycarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower cycloalkyloxy
group. Specific examples thereof include cyclopropyloxycarbonyl,
cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl,
cycloheptyloxycarbonyl and cyclooctyloxycarbonyl groups.

[0061]The "aryloxycarbonyl group" refers to a group formed by replacing
the hydrogen atom of a formyl group with an aryloxy group. Specific
examples thereof include phenoxycarbonyl, naphthoxycarbonyl,
anthryloxycarbonyl and phenanthryloxycarbonyl groups and the like.

[0062]The "heterocyclic oxycarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a heterocyclic oxy
group.

[0063]The "lower alkylaminocarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkylamino
group. Specific examples thereof include methylaminocarbonyl,
ethylaminocarbonyl, propylaminocarbonyl, dimethylaminocarbonyl,
diethylaminocarbonyl and ethylmethylaminocarbonyl groups and the like.

[0064]The "lower alkenylaminocarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkenylamino
group. Specific examples thereof include vinylaminocarbonyl,
propenylaminocarbonyl, butenylaminocarbonyl, pentenylaminocarbonyl,
hexenylaminocarbonyl, heptenylaminocarbonyl, octenylaminocarbonyl,
isopropenylaminocarbonyl, 2-methyl-1-propenylaminocarbonyl,
2-methyl-2-butenylaminocarbonyl, divinylaminocarbonyl and
methyl(vinyl)aminocarbonyl groups and the like.

[0065]The "lower alkynylaminocarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a lower alkynylamino
group. Specific examples thereof include ethynylaminocarbonyl,
propynylaminocarbonyl, butynylaminocarbonyl, pentynylaminocarbonyl,
hexynylaminocarbonyl, heptynylaminocarbonyl, octynylaminocarbonyl,
isobutynylaminocarbonyl, isopentynylaminocarbonyl,
diethynylaminocarbonyl, ethynyl(methyl)aminocarbonyl and
ethynyl(vinyl)aminocarbonyl groups and the like.

[0066]The "lower cycloalkylaminocarbonyl group" refers to a group formed
by replacing the hydrogen atom of a formyl group with a lower
cycloalkylamino group. Specific examples thereof include
cyclopropylaminocarbonyl, cyclobutylaminocarbonyl,
cyclopentylaminocarbonyl, cyclohexylaminocarbonyl,
cycloheptylaminocarbonyl, cyclooctylaminocarbonyl,
dicyclohexylaminocarbonyl, cyclohexyl(methyl)aminocarbonyl,
cyclohexyl(vinyl)aminocarbonyl and cyclohexyl(ethynyl)aminocarbonyl
groups and the like.

[0067]The "arylaminocarbonyl group" refers to a group formed by replacing
the hydrogen atom of a formyl group with an arylamino group. Specific
examples thereof include phenylaminocarbonyl, naphthylaminocarbonyl,
anthrylaminocarbonyl, phenanthrylaminocarbonyl, diphenylaminocarbonyl,
methylphenylaminocarbonyl ethylphenylaminocarbonyl,
phenyl(vinyl)aminocarbonyl, ethynyl(phenyl)aminocarbonyl and
cyclohexyl(phenyl)aminocarbonyl groups and the like.

[0068]The "heterocyclic aminocarbonyl group" refers to a group formed by
replacing the hydrogen atom of a formyl group with a heterocyclic amino
group.

[0069]The "lower alkylsulfonyl group" refers to a group formed by
replacing the hydroxy group of a sulfonic acid group with a lower alkyl
group. Specific examples thereof include methylsulfonyl, ethylsulfonyl,
n-propylsulfonyl, n-butylsulfonyl, n-pentylsulfonyl, n-hexylsulfonyl,
n-heptylsulfonyl, n-octylsulfonyl, isopropylsulfonyl, isobutylsulfonyl,
sec-butylsulfonyl, tert-butylsulfonyl and isopentylsulfonyl groups and
the like.

[0070]The "lower alkenylsulfonyl group" refers to a group formed by
replacing the hydroxy group of a sulfonic acid group with a lower alkenyl
group. Specific examples thereof include vinylsulfonyl, propenylsulfonyl,
butenylsulfonyl, pentenylsulfonyl, hexenylsulfonyl, heptenylsulfonyl,
octenylsulfonyl, isopropenylsulfonyl, 2-methyl-1-propenylsulfonyl and
2-methyl-2-butenylsulfonyl groups and the like.

[0071]The "lower alkynylsulfonyl group" refers to a group formed by
replacing the hydroxy group of a sulfonic acid group with a lower alkynyl
group. Specific examples thereof include ethynylsulfonyl,
propynylsulfonyl, butynylsulfonyl, pentynylsulfonyl, hexynylsulfonyl,
heptynylsulfonyl, octynylsulfonyl, isobutynylsulfonyl and
isopentynylsulfonyl groups and the like.

[0072]The "lower cycloalkylsulfonyl group" refers to a group formed by
replacing the hydroxy group of a sulfonic acid group with a lower
cycloalkyl group. Specific examples thereof include cyclopropylsulfonyl,
cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl,
cycloheptylsulfonyl and cyclooctylsulfonyl groups.

[0073]The "arylsulfonyl group" refers to a group formed by replacing the
hydroxy group of a sulfonic acid group with an aryl group. Specific
examples thereof include phenylsulfonyl, naphthylsulfonyl,
anthrylsulfonyl and phenanthrylsulfonyl groups and the like.

[0074]The "heterocyclic sulfonyl group" refers to a group formed by
replacing the hydroxy group of a sulfonic acid group with a heterocyclic
group.

[0075]The "3- to 8-membered nitrogen-containing heterocyclic ring" refers
to a saturated monocyclic heterocyclic ring containing one or two
nitrogen atoms in the ring. Specific examples thereof include aziridine,
azetidine, pyrrolidine, piperidine, imidazolidine, pyrazolidine,
piperazine and morpholine rings and the like.

[0077]The "ester of a hydroxy group" refers to an ester formed from a
hydroxy group and a carboxylic acid and/or a group represented by
--OCO--R.

[0078]Herein, R represents a hydrogen atom, a lower alkyl group which may
have at least a substituent, a lower alkenyl group which may have at
least a substituent, a lower alkynyl group which may have at least a
substituent, a lower cycloalkyl group which may have at least a
substituent, an aryl group which may have at least a substituent, a
heterocyclic group which may have at least a substituent, a lower alkoxy
group which may have at least a substituent, a lower alkenyloxy group
which may have at least a substituent, a lower alkynyloxy group which may
have at least a substituent, a lower cycloalkyloxy group which may have
at least a substituent, an aryloxy group which may have at least a
substituent, a heterocyclic oxy group which may have at least a
substituent, an amino group, a lower alkylamino group which may have at
least a substituent, a lower cycloalkylamino group which may have at
least a substituent, an arylamino group which may have at least a
substituent or a heterocyclic amino group which may have at least a
substituent. R is the same as below.

[0079]The "ester of a mercapto group" refers to a thioester formed from a
mercapto group and a carboxylic acid and/or a group represented by
--SCO--R.

[0080]Herein, R is the same as the above.

[0081]The "amide of an amino group" refers to an amide formed from an
amino group and a carboxylic acid and/or a group represented by
--NHCO--R. Herein, R is the same as the above.

[0082]The "amide of a lower alkylamino group" refers to an amide formed
from a lower alkylamino group and a carboxylic acid and/or a group
represented by --NR'CO--R. Herein, R' represents a lower alkyl group
which may have at least a substituent, and R is the same as the above.

[0083]The "amide of a lower cycloalkylamino group" refers to an amide
formed from a lower cycloalkylamino group and a carboxylic acid and/or a
group represented by --NR''CO--R. Herein, R'' represents a lower
cycloalkyl group which may have at least a substituent, and R is the same
as the above.

[0084]The "amide of an arylamino group" refers to an amide formed from an
arylamino group and a carboxylic acid and/or a group represented by
--NR'''CO--R.

[0085]Herein, R''' represents an aryl group which may have at least a
substituent, and R is the same as the above.

[0086]The "amide of a heterocyclic amino group" refers to an amide formed
from a heterocyclic amino group and a carboxylic acid and/or a group
represented by --NR''''CO--R. Herein, R'''' represents a heterocyclic
group which may have at least a substituent, and R is the same for the
above.

[0087]The "carboxylic acid" refers to a saturated aliphatic carboxylic
acid, an unsaturated aliphatic carboxylic acid, an aryl carboxylic acid,
a heterocyclic carboxylic acid or the like represented by RaCOOH
(Ra represents a hydrogen atom, a lower alkyl group which may have
at least a substituent, a lower alkenyl group which may have at least a
substituent, a lower alkynyl group which may have at least a substituent,
a lower cycloalkyl group which may have at least a substituent, an aryl
group which may have at least a substituent, a heterocyclic group which
may have at least a substituent and the like). Specific examples thereof
include saturated aliphatic carboxylic acids such as formic acid, acetic
acid, propionic acid, butyric acid, isobutyric acid, valeric acid,
isovaleric acid, pivalic acid, cyclopropanecarboxylic acid,
cyclobutanecarboxylic acid, cyclopentanecarboxylic acid and
cyclohexanecarboxylic acid; unsaturated aliphatic carboxylic acids such
as acrylic acid, propionic acid, crotonic acid, cinnamic acid,
cyclopentenecarboxylic acid and cyclohexenecarboxylic acid; aryl
carboxylic acids such as benzoic acid, phthalic acid, isophthalic acid,
terephthalic acid, naphthoic acid and toluic acid; heterocyclic
carboxylic acids such as furancarboxylic acid, thiophenecarboxylic acid,
nicotinic acid and isonicotinic acid; and the like.

[0088]The "ester of a carboxy group" refers to an ester formed from a
carboxy group and an alcohol or a phenol.

[0089]The "ester of a sulfonic acid group" refers to an ester formed from
a sulfonic acid group and an alcohol or a phenol.

[0090]The "alcohol" refers to a saturated aliphatic hydroxy compound, an
unsaturated aliphatic hydroxy compound, a heterocyclic hydroxyl compound
or the like represented by RbOH (Rb represents a lower alkyl
group which may have at least a substituent, a lower alkenyl group which
may have at least a substituent, a lower alkynyl group which may have at
least a substituent, a lower cycloalkyl group which may have at least a
substituent, a heterocyclic group which may have at least a substituent
or the like). Specific examples thereof include saturated aliphatic
hydroxy compounds such as methanol, ethanol, propanol, butanol,
isopropanol, cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol,
benzylalcohol and phenethylalcohol; unsaturated aliphatic hydroxy
compounds such as vinyl alcohol, allylalcohol, propagylalcohol,
cyclopentenol and cyclohexenol; heterocyclic hydroxy compounds such as
hydroxypiperidine and hydroxytetrahydropyran.

[0091]The "phenol" refers to an aryl hydroxy compound, a heterocyclic
hydroxyl compound or the like represented by RcOH (Rc
represents an aryl group which may have at least a substituent, a
heterocyclic group which may have at least a substituent or the like).
Specific examples thereof include aryl hydroxyl compounds such as phenol,
naphthol, anthrol and phenanthrol; heterocyclic hydroxyl compounds such
as hydroxypyridine, hydroxyfuran and hydroxythiophen.

[0092]The "amide of a carboxy group" refers to an acid amide formed from a
carboxy group and an amine.

[0093]The "amide of a sulfonic acid group" refers to an acid amide formed
from a sulfonic acid group and an amine.

[0094]The "amine" refers to ammonia, a saturated aliphatic amine compound,
an unsaturated aliphatic amine compound, an aryl amine compound, a
heterocyclic amine compound, a saturated cyclic amine compound or the
like represented by HNRdRe (Rd and Re may be the same
or different and represent a hydrogen atom, a lower alkyl group which may
have at least a substituent, a lower alkenyl group which may have at
least a substituent, a lower alkynyl group which may have at least a
substituent, a lower cycloalkyl group which may have at least a
substituent, an aryl group which may have at least a substituent, a
heterocyclic group or the like, or Rd and Re may be combined
together to form a saturated cyclic amine). Specific examples thereof
include ammonia; saturated aliphatic amine compounds such as methylamine,
ethylamine, propylamine, pentylamine, dimethylamine, diethylamine,
ethylmethylamine, cyclopropylamine, cyclobutylamine, cyclopentylamine,
cyclohexylamine, benzylamine and phenetylamine; unsaturated aliphatic
amine compounds such as allylamine and propagylamine; aryl amine
compounds such as phenylamine, naphthylamine, anthrylamine,
phenanthrylamine, diphenylamine, methylphenylamine and ethylphenylamine;
heterocyclic amine compounds such as furylamine, thienylamine,
pyrrolidylamine, pyridylamine, quinolylamine and methylpyridylamine;
saturated cyclic amine compounds such as aziridine, azetidine,
pyrrolidine, piperidine and 4-methylpiperidine.

[0095]The "lower alkyl group which may have at least a substituent",
"lower alkenyl group which may have at least a substituent", "lower
alkynyl group which may have at least a substituent", "lower alkoxy group
which may have at least a substituent", "lower alkylthio group which may
have at least a substituent", "lower alkylamino group which may have at
least a substituent", "lower alkylcarbonyl group which may have at least
a substituent", "lower alkenylcarbonyl group which may have at least a
substituent", "lower alkynylcarbonyl group which may have at least a
substituent", "lower alkoxycarbonyl group which may have at least a
substituent", "lower alkenyloxycarbonyl group which may have at least a
substituent", "lower alkynyloxycarbonyl group which may have at least a
substituent", "lower alkylaminocarbonyl group which may have at least a
substituent", "lower alkenylaminocarbonyl group which may have at least a
substituent", "lower alkynylaminocarbonyl group which may have at least a
substituent", "lower alkylsulfonyloxy group which may have at least a
substituent", "lower alkenylsulfonyloxy group which may have at least a
substituent", "lower alkynylsulfonyloxy group which may have at least a
substituent" and "amide of lower alkylamino group which may have at least
a substituent" refer to a "lower alkyl group", a "lower alkenyl group", a
"lower alkynyl group", a "lower alkoxy group", a "lower alkylthio group",
a "lower alkylamino group", a "lower alkylcarbonyl group", a "lower
alkenylcarbonyl group", a "lower alkynylcarbonyl group", a "lower
alkoxycarbonyl group", a "lower alkenyloxycarbonyl group", a "lower
alkynyloxycarbonyl group", a "lower alkylaminocarbonyl group", a "lower
alkenylaminocarbonyl group", a "lower alkynylaminocarbonyl group", a
"lower alkylsulfonyl group", a "lower alkenylsulfonyl group", a "lower
alkynylsulfonyl group" and an "amide of the lower alkylamino group" which
may have one or a plurality of substituents selected from the following
al group, respectively.

[α1 Group]

[0096]A halogen atom, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower
alkoxy group, a lower alkoxy group substituted by a halogen atom, a lower
alkenyloxy group, a lower alkynyloxy group, a lower cycloalkyloxy group,
an aryloxy group, a heterocyclic oxy group, a mercapto group, an ester of
a mercapto group, a lower alkylthio group, a lower alkenylthio group, a
lower alkynylthio group, a lower cycloalkylthio group, an arylthio group,
a heterocyclic thio group, an amino group, a lower alkylamino group, a
lower cycloalkylamino group, an arylamino group, a heterocyclic amino
group, an amide of an amino group, an amide of a lower alkylamino group,
an amide of a lower cycloalkylamino group, an amide of an arylamino
group, an amide of a heterocyclic amino group, a formyl group, a lower
alkylcarbonyl group, a lower alkenylcarbonyl group, a lower
alkynylcarbonyl group, a lower cycloalkylcarbonyl group, an arylcarbonyl
group, a heterocyclic carbonyl group, a carboxy group, an ester of a
carboxy group, an amide of a carboxy group, a lower alkylsulfinyl group,
an arylsulfinyl group, a lower alkylsulfonyl group, a lower
cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl
group, a sulfinic acid group, an ester of a sulfinic acid group, an amide
of a sulfinic acid group, a sulfonic acid group, an ester of a sulfonic
acid group, an amide of a sulfonic acid group, a nitro group and a cyano
group.

[0097]The "lower cycloalkyl group which may have at least a substituent",
"aryl group which may have at least a substituent", "heterocyclic group
which may have at least a substituent", "lower cycloalkyloxy group which
may have at least a substituent", "aryloxy group which may have at least
a substituent", "heterocyclic oxy group which may have at least a
substituent", "lower cycloalkylthio group which may have at least a
substituent", "arylthio group which may have at least a substituent",
"heterocyclic thio group which may have at least a substituent", "lower
cycloalkylamino group which may have at least a substituent", "arylamino
group which may have at least a substituent", "heterocyclic amino group
which may have at least a substituent", "lower cycloalkylcarbonyl group
which may have at least a substituent", "arylcarbonyl group which may
have at least a substituent", "heterocyclic carbonyl group which may have
at least a substituent", "lower cycloalkyloxycarbonyl group which may
have at least a substituent", "aryloxycarbonyl group which may have at
least a substituent", "heterocyclic oxycarbonyl group which may have at
least a substituent", "lower cycloalkylaminocarbonyl group which may have
at least a substituent", "arylaminocarbonyl group which may have at least
a substituent", "heterocyclic aminocarbonyl group which may have at least
a substituent", "lower cycloalkylsulfonyl group which may have at least a
substituent", "arylsulfonyl group which may have at least a substituent",
"heterocyclic sulfonyl group which may have at least a substituent",
"amide of lower cycloalkylamino group which may have at least a
substituent", "amide of arylamino group which may have at least a
substituent" and "amide of heterocyclic amino group which may have at
least a substituent" refer to a "lower cycloalkyl group", an "aryl
group", a "heterocyclic group", a "lower cycloalkyloxy group", an
"aryloxy group", a "heterocyclic oxy group", a "lower cycloalkylthio
group", an "arylthio group", a "heterocyclic thio group", a "lower
cycloalkylamino group", an "arylamino group", a "heterocyclic amino
group", a "lower cycloalkylcarbonyl group", an "arylcarbonyl group", a
"heterocyclic carbonyl group", an "lower cycloalkyloxycarbonyl group", an
"aryloxycarbonyl group", a "heterocyclic oxycarbonyl group", a "lower
cycloalkylaminocarbonyl group", an "arylaminocarbonyl group", a
"heterocyclic aminocarbonyl group", a "lower cycloalkylsulfonyl group",
an "arylsulfonyl group", a "heterocyclic sulfonyl group", an "amide of
lower cycloalkylamino group", an "amide of arylamino group" and an "amide
of heterocyclic amino group" which may have one or a plurality of
substituents selected from the following β1 group,
respectively.

[β1 Group]

[0098]A halogen atom, a lower alkyl group, a lower alkyl group substituted
by a halogen atom, a lower alkenyl group, a lower alkynyl group, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group,
an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group
substituted by a halogen atom, a lower alkenyloxy group, a lower
alkynyloxy group, a lower cycloalkyloxy group, an aryloxy group, a
heterocyclic oxy group, a mercapto group, an ester of a mercapto group, a
lower alkylthio group, a lower alkenylthio group, a lower alkynylthio
group, a lower cycloalkylthio group, an arylthio group, a heterocyclic
thio group, an amino group, a lower alkylamino group, a lower
cycloalkylamino group, an arylamino group, a heterocyclic amino group, an
amide of an amino group, an amide of a lower alkylamino group, an amide
of a lower cycloalkylamino group, an amide of an arylamino group, an
amide of a heterocyclic amino group, a formyl group, a lower
alkylcarbonyl group, a lower alkenylcarbonyl group, a lower
alkynylcarbonyl group, a lower cycloalkylcarbonyl group, an arylcarbonyl
group, a heterocyclic carbonyl group, a carboxy group, an ester of a
carboxy group, an amide of a carboxy group, a lower alkylsulfinyl group,
an arylsulfinyl group, a lower alkylsulfonyl group, a lower
cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl
group, a sulfinic acid group, an ester of a sulfinic acid group, an amide
of a sulfinic acid group, a sulfonic acid group, an ester of a sulfonic
acid group, an amide of a sulfonic acid group, a nitro group, a cyano
group, a lower alkylaminocarbonyloxy group and an arylaminocarbonyloxy
group.

[0099]The term "a plurality of groups" as used herein means that each
group may be the same or different and the number of groups is preferably
2. Further, a hydrogen atom and a halogen atom are also included in the
concept of the "group".

[0100]The "glucocorticoid receptor modulator" as used herein refers to a
modulator that exhibits a pharmaceutical action by binding to
glucocorticoid receptor. Examples thereof include glucocorticoid receptor
agonists, glucocorticoid receptor antagonists and the like.

[0102]In the case where there are geometrical isomers or optical isomers
in the present compound, these isomers are also included in the scope of
the present invention.

[0103]Further, the present compound may be in the form of a hydrate or a
solvate.

[0104]In the case where there is proton tautomerism in the present
compound, the tautomeric isomers thereof are also included in the present
invention.

[0105]In the case where there are crystalline polymorphisms in the present
compound, the crystalline polymorphisms thereof are also included in the
present invention.

[0106](a) Preferred examples of the present compound include compounds in
which the respective groups are groups as defined below and salts thereof
in the compounds represented by the general formula (1) and salts
thereof.

[0107]In the general formula (1),

[0108](a1) R1 represents a halogen atom, a lower alkyl group, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group,
an ester of a hydroxy group, a lower alkoxy group, a lower cycloalkyloxy
group, an aryloxy group, a heterocyclic oxy group, a mercapto group, an
ester of a mercapto group, a lower alkylthio group, a lower
cycloalkylthio group, an arylthio group, a heterocyclic thio group, an
amino group, a lower alkylamino group, a lower cycloalkylamino group, an
arylamino group, a heterocyclic amino group, an amide of an amino group,
an amide of a lower alkylamino group, an amide of a lower cycloalkylamino
group, an amide of an arylamino group, an amide of a heterocyclic amino
group, a lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a carboxy group, an
ester of a carboxy group, an amide of a carboxy group, a lower
alkylsulfonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl
group, a heterocyclic sulfonyl group, a sulfonic acid group, an ester of
a sulfonic acid group, an amide of a sulfonic acid group, a nitro group
or a cyano group;

[0109]in the case where R1 is a lower alkyl group, a lower alkoxy
group, a lower alkylthio group, a lower alkylamino group, an amide of a
lower alkylamino group, a lower alkylcarbonyl group or a lower
alkylsulfonyl group, the lower alkyl group, lower alkoxy group, lower
alkylthio group, lower alkylamino group, amide of a lower alkylamino
group, lower alkylcarbonyl group or lower alkylsulfonyl group may have
one or a plurality of groups selected from a halogen atom, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group,
an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group
substituted with a halogen atom, a lower cycloalkyloxy group, an aryloxy
group, a heterocyclic oxy group, a lower alkylthio group, a lower
cycloalkylthio group, an arylthio group, a heterocyclic thio group, an
amino group, a lower alkylamino group, a lower cycloalkylamino group, an
arylamino group, a heterocyclic amino group, an amide of an amino group,
an amide of a lower alkylamino group, an amide of a lower cycloalkylamino
group, an amide of an arylamino group, an amide of a heterocyclic amino
group, a lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a carboxy group, an
ester of a carboxy group, an amide of a carboxy group, a lower
alkylsulfonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl
group, a heterocyclic sulfonyl group, a sulfonic acid group, an ester of
a sulfonic acid group, an amide of a sulfonic acid group, a nitro group
and a cyano group as substituents;

[0110]in the case where R1 is a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower cycloalkyloxy group, an aryloxy
group, a heterocyclic oxy group, a lower cycloalkylthio group, an
arylthio group, a heterocyclic thio group, a lower cycloalkylamino group,
an arylamino group, a heterocyclic amino group, an amide of a lower
cycloalkylamino group, an amide of an arylamino group, an amide of a
heterocyclic amino group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a lower
cycloalkylsulfonyl group, an arylsulfonyl group or a heterocyclic
sulfonyl group, the lower cycloalkyl group, aryl group, heterocyclic
group, lower cycloalkyloxy group, aryloxy group, heterocyclic oxy group,
lower cycloalkylthio group, arylthio group, heterocyclic thio group,
lower cycloalkylamino group, arylamino group, heterocyclic amino group,
amide of a lower cycloalkylamino group, amide of an arylamino group,
amide of a heterocyclic amino group, lower cycloalkylcarbonyl group,
arylcarbonyl group, heterocyclic carbonyl group, lower cycloalkylsulfonyl
group, arylsulfonyl group or heterocyclic sulfonyl group may have one or
a plurality of groups selected from a halogen atom, a lower alkyl group,
a lower alkyl group substituted with a halogen atom, a hydroxy group, an
ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group
substituted with a halogen atom, a lower alkylthio group, an amino group,
a lower alkylamino group, an amide of an amino group, an amide of a lower
alkylamino group, a lower alkylcarbonyl group, a carboxy group, an ester
of a carboxy group, an amide of a carboxy group, a lower alkylsulfonyl
group, a sulfonic acid group, an ester of a sulfonic acid group, an amide
of a sulfonic acid group, a nitro group and a cyano group as
substituents; and/or

[0111](a2) p represents an integer of 0 to 3;

[0112]in the case where p is 2 or 3, each R1 may be the same or
different; and/or

[0113](a3) R2 represents a halogen atom, a lower alkyl group, a
hydroxy group or a lower alkoxy group; and/or

[0114](a4) q represents an integer of 0 to 2;

[0115]in the case where q is 2, each R2 may be the same or different;
and/or

[0116](a5) R3 represents a hydrogen atom, a lower alkyl group, a
lower alkenyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl
group or an arylcarbonyl group;

[0117]in the case where R3 is a lower alkyl group or a lower
alkylcarbonyl group, the lower alkyl group or lower alkylcarbonyl group
may have one or a plurality of groups selected from a halogen atom and an
aryl group as substituents;

[0118]in the case where R3 is an arylcarbonyl group, the arylcarbonyl
group may have one or a plurality of groups selected from a halogen atom,
a lower alkyl group, a lower alkyl group substituted with a halogen atom,
a lower alkoxy group and a lower alkoxy group substituted with a halogen
atom as substituents; and/or

[0119](a6) R4 and R5 may be the same or different and represent
a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl
group, aryl or a heterocyclic group;

[0120]in the case where R4 or R5 is a lower alkyl group, the
lower alkyl group may have one or a plurality of groups selected from a
halogen atom, a lower cycloalkyl group, an aryl group, a heterocyclic
group, a hydroxy group, an ester of a hydroxy group, a lower alkoxy
group, a lower alkoxy group substituted with a halogen atom, a lower
cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a lower
alkylthio group, a lower cycloalkylthio group, an arylthio group, a
heterocyclic thio group, an amino group, a lower alkylamino group, a
lower cycloalkylamino group, an arylamino group, a heterocyclic amino
group, an amide of an amino group, an amide of a lower alkylamino group,
an amide of a lower cycloalkylamino group, an amide of an arylamino
group, an amide of a heterocyclic amino group, a lower alkylcarbonyl
group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a
heterocyclic carbonyl group, a carboxy group, an ester of a carboxy
group, an amide of a carboxy group, a nitro group and a cyano group as
substituents;

[0121]in the case where R4 or R5 is a lower cycloalkyl group,
aryl or a heterocyclic group, the lower cycloalkyl group, aryl or
heterocyclic group may have one or a plurality of groups selected from a
halogen atom, a lower alkyl group, a lower alkyl group substituted with a
halogen atom, a hydroxy group, an ester of a hydroxy group, a lower
alkoxy group, a lower alkoxy group substituted with a halogen atom, a
lower alkylthio group, an amino group, a lower alkylamino group, an amide
of an amino group, an amide of a lower alkylamino group, a lower
alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an
amide of a carboxy group, a lower alkylsulfonyl group, a sulfonic acid
group, an ester of a sulfonic acid group, an amide of a sulfonic acid
group, a nitro group and a cyano group as substituents;

[0122]R4 and R5 may be combined together to form a 3- to
8-membered lower cycloalkane ring; and/or

[0123](a7) R6 represents a hydrogen atom, a lower alkyl group, a
lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group;

[0124]in the case where R6 is a lower alkyl group, a lower alkenyl
group, a lower alkynyl group or a lower cycloalkyl group, the lower alkyl
group, lower alkenyl group, lower alkynyl group or lower cycloalkyl group
may have one or a plurality of groups selected from a halogen atom and an
aryl group as substituents; and/or

[0125](a8) A represents a lower alkylene group which may be substituted
with a hydroxy group or a halogen atom; and/or

[0126](a9) R7 represents OR8, NR8R9 or SR8;

[0127]R8 and R9 may be the same or different and represent a
hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower cycloalkyl group, an aryl group, a heterocyclic
group, a formyl group, a lower alkylcarbonyl group, a lower
alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower
cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl
group, a carboxy group, a lower alkoxycarbonyl group, a lower
alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, a lower
cycloalkyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclic
oxycarbonyl group, a lower alkylsulfonyl group, a lower alkenylsulfonyl
group, a lower alkenylsulfonyl group, a lower cycloalkylsulfonyl group,
an arylsulfonyl group, a heterocyclic sulfonyl group, an aminocarbonyl
group, a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl
group, a lower alkynylaminocarbonyl group, a lower
cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a
heterocyclic aminocarbonyl group;

[0128]in the case where R8 or R9 is a lower alkyl group, a lower
alkenyl group, a lower alkynyl group, a lower alkylcarbonyl group, a
lower alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower
alkoxycarbonyl group, a lower alkenyloxycarbonyl group, a lower
alkynyloxycarbonyl group, a lower alkylsulfonyl group, a lower
alkenylsulfonyl group, a lower alkynylsulfonyl group, a lower
alkylaminocarbonyl group, a lower alkenylaminocarbonyl group or a lower
alkynylaminocarbonyl group, the lower alkyl group, lower alkenyl group,
lower alkynyl group, lower alkylcarbonyl group, lower alkenylcarbonyl
group, lower alkynylcarbonyl group, lower alkoxycarbonyl group, lower
alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower
alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl
group, lower alkylaminocarbonyl group, lower alkenylaminocarbonyl group
or lower alkynylaminocarbonyl group may have one or a plurality of groups
selected from a halogen atom, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower
alkoxy group, a lower alkoxy group substituted with a halogen atom, a
lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a
lower alkylthio group, a lower cycloalkylthio group, an arylthio group, a
heterocyclic thio group, an amino group, a lower alkylamino group, a
lower cycloalkylamino group, an arylamino group, a heterocyclic amino
group, an amide of an amino group, an amide of a lower alkylamino group,
an amide of a lower cycloalkylamino group, an amide of an arylamino
group, an amide of a heterocyclic amino group, a lower alkylcarbonyl
group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a
heterocyclic carbonyl group, a carboxy group, an ester of a carboxy
group, an amide of a carboxy group, a lower alkylsulfonyl group, a lower
cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl
group, a sulfonic acid group, an ester of a sulfonic acid group, an amide
of a sulfonic acid group, a nitro group and a cyano group as
substituents;

[0129]in the case where R8 or R9 is a lower cycloalkyl group, an
aryl group, a heterocyclic group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a lower
cycloalkyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclic
oxycarbonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl
group, a heterocyclic sulfonyl group, a lower cycloalkylaminocarbonyl
group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group,
the lower cycloalkyl group, aryl group, heterocyclic group, lower
cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl
group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group,
heterocyclic oxycarbonyl group, lower cycloalkylsulfonyl group,
arylsulfonyl group, heterocyclic sulfonyl group, lower
cycloalkylaminocarbonyl group, arylaminocarbonyl group or heterocyclic
aminocarbonyl group may have one or a plurality of groups selected from a
halogen atom, a lower alkyl group, a lower alkyl group substituted with a
halogen atom, a lower alkyl group substituted with a hydroxy group, a
lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, an
aryl group, a heterocyclic group, a hydroxy group, an ester of a hydroxy
group, a lower alkoxy group, a lower alkoxy group substituted with a
halogen atom, a lower alkenyloxy group, a lower alkynyloxy group, a lower
cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, a lower
alkylthio group, a lower cycloalkylthio group, an arylthio group, a
heterocyclic thio group, an amino group, a lower alkylamino group, a
lower cycloalkylamino group, an arylamino group, a heterocyclic amino
group, an amide of an amino group, an amide of a lower alkylamino group,
an amide of a lower cycloalkylamino group, an amide of an arylamino
group, an amide of a heterocyclic amino group, a lower alkylcarbonyl
group, a lower cycloalkylcarbonyl group, an arylcarbonyl group, a
heterocyclic carbonyl group, a carboxy group, an ester of a carboxy
group, an amide of a carboxy group, a lower alkylsulfonyl group, a lower
cycloalkylsulfonyl group, an arylsulfonyl group, a heterocyclic sulfonyl
group, a sulfonic acid group, an ester of a sulfonic acid group, an amide
of a sulfonic acid group, a nitro group and a cyano group as
substituents;

[0130]in the case where R7 is NR8R9, R8 and R9
may be combined together to form a 5- or 6-membered nitrogen-containing
heterocyclic ring; and/or

[0131](a10) X represents O or S.

[0132]That is, in the compounds represented by the general formula (1),
preferred examples include compounds that comprises one or a combination
of two or more selected from the above (a1), (a2), (a3), (a4), (a5),
(a6), (a7), (a8), (a9) and (a10), and salts thereof.

[0133](b) More preferred examples of the present compound include
compounds in which the respective groups are groups as defined below and
salts thereof in the compounds represented by the general formula (1) and
salts thereof.

[0134]In the general formula (1),

[0135](b1) R1 represents a halogen atom, a lower alkyl group, a
hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower
alkylthio group, an amino group, a lower alkylamino group, an amide of an
amino group, an amide of a lower alkylamino group, a lower alkylcarbonyl
group, a carboxy group, an ester of a carboxy group, an amide of a
carboxy group, a lower alkylsulfonyl group, a nitro group or a cyano
group;

[0136]in the case where R1 is a lower alkyl group, a lower alkoxy
group, a lower alkylthio group, a lower alkylamino group, an amide of a
lower alkylamino group, a lower alkylcarbonyl group or a lower
alkylsulfonyl group, the lower alkyl group, lower alkoxy group, lower
alkylthio group, lower alkylamino group, amide of a lower alkylamino
group, lower alkylcarbonyl group or lower alkylsulfonyl group may have
one or a plurality of groups selected from a halogen atom, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a hydroxy group,
an ester of a hydroxy group, a lower alkoxy group, a lower alkoxy group
substituted with a halogen atom, a lower cycloalkyloxy group, an aryloxy
group, a heterocyclic oxy group, a lower alkylthio group, a lower
cycloalkylthio group, an arylthio group, a heterocyclic thio group, an
amino group, a lower alkylamino group, a lower cycloalkylamino group, an
arylamino group, a heterocyclic amino group, an amide of an amino group,
an amide of a lower alkylamino group, an amide of a lower cycloalkylamino
group, an amide of an arylamino group, an amide of a heterocyclic amino
group, a lower alkylcarbonyl group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a carboxy group, an
ester of a carboxy group, an amide of a carboxy group, a lower
alkylsulfonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl
group, a heterocyclic sulfonyl group, a sulfonic acid group, an ester of
a sulfonic acid group, an amide of a sulfonic acid group, a nitro group
and a cyano group as substituents; and/or

[0137](b2) p represents an integer of 0 to 3;

[0138]in the case where p is 2 or 3, each R1 may be the same or
different; and/or

[0139](b3) q represents 0; and/or

[0140](b4) R3 represents a hydrogen atom, a lower alkyl group, a
lower alkenyl group, a lower alkylcarbonyl group, a lower alkenylcarbonyl
group or an arylcarbonyl group;

[0141]in the case where R3 is a lower alkyl group, the lower alkyl
group may have one or a plurality of aryl groups as substituents;

[0142]in the case where R3 is an arylcarbonyl group, the arylcarbonyl
group may have one or a plurality of groups selected from a halogen atom
and a lower alkyl group as substituents; and/or

[0143](b5) R4 and R5 may be the same or different and represent
a hydrogen atom, a halogen atom, a lower alkyl group, a lower cycloalkyl
group, aryl or a heterocyclic group;

[0144]in the case where R4 or R5 is a lower alkyl group, the
lower alkyl group may have one or a plurality of groups selected from a
halogen atom, a hydroxy group, an ester of a hydroxy group, a lower
alkoxy group, a lower alkoxy group substituted with a halogen atom, a
lower alkylthio group, an amino group, a lower alkylamino group, an amide
of an amino group, an amide of a lower alkylamino group, a lower
alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an
amide of a carboxy group, a nitro group and a cyano group as
substituents;

[0145]in the case where R4 or R5 is a lower cycloalkyl group,
aryl or a heterocyclic group, the lower cycloalkyl group, aryl or
heterocyclic group may have one or a plurality of groups selected from a
halogen atom, a lower alkyl group, a lower alkyl group substituted with a
halogen atom, a hydroxy group, an ester of a hydroxy group, a lower
alkoxy group, a lower alkoxy group substituted with a halogen atom, a
lower alkylthio group, an amino group, a lower alkylamino group, an amide
of an amino group, an amide of a lower alkylamino group, a lower
alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an
amide of a carboxy group, a lower alkylsulfonyl group, a nitro group and
a cyano group as substituents;

[0146]R4 and R5 may be combined together to form a 3- to
8-membered lower cycloalkane ring; and/or

[0147](b6) R6 represents a hydrogen atom, a lower alkyl group, a
lower alkenyl group, a lower alkynyl group or a lower cycloalkyl group;

[0148]in the case where R6 is a lower alkyl group, a lower alkenyl
group, a lower alkynyl group or a lower cycloalkyl group, the lower alkyl
group, lower alkenyl group, lower alkynyl group or lower cycloalkyl group
may have one or a plurality of groups selected from a halogen atom and an
aryl group as substituents; and/or

[0149](b7) A represents a lower alkylene group; and/or

[0150](b8) R7 represents OR8, NR8R9 or SR8;

[0151]R8 and R9 may be the same or different and represent a
hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower
alkynyl group, a lower cycloalkyl group, an aryl group, a heterocyclic
group, a formyl group, a lower alkylcarbonyl group, a lower
alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower
cycloalkylcarbonyl group, an arylcarbonyl group, a heterocyclic carbonyl
group, a carboxy group, a lower alkoxycarbonyl group, a lower
alkenyloxycarbonyl group, a lower alkynyloxycarbonyl group, a lower
cycloalkyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclic
oxycarbonyl group, a lower alkylsulfonyl group, a lower alkenylsulfonyl
group, a lower alkynylsulfonyl group, a lower cycloalkylsulfonyl group,
an arylsulfonyl group, a heterocyclic sulfonyl group, an aminocarbonyl
group, a lower alkylaminocarbonyl group, a lower alkenylaminocarbonyl
group, a lower alkynylaminocarbonyl group, a lower
cycloalkylaminocarbonyl group, an arylaminocarbonyl group or a
heterocyclic aminocarbonyl group;

[0152]in the case where R8 or R9 is a lower alkyl group, a lower
alkenyl group, a lower alkynyl group, a lower alkylcarbonyl group, a
lower alkenylcarbonyl group, a lower alkynylcarbonyl group, a lower
alkoxycarbonyl group, a lower alkenyloxycarbonyl group, a lower
alkynyloxycarbonyl group, a lower alkylsulfonyl group, a lower
alkenylsulfonyl group, a lower alkynylsulfonyl group, a lower
alkylaminocarbonyl group, a lower alkenylaminocarbonyl group or a lower
alkynylaminocarbonyl group, the lower alkyl group, lower alkenyl group,
lower alkynyl group, lower alkylcarbonyl group, lower alkenylcarbonyl
group, lower alkynylcarbonyl group, lower alkoxycarbonyl group, lower
alkenyloxycarbonyl group, lower alkynyloxycarbonyl group, lower
alkylsulfonyl group, lower alkenylsulfonyl group, lower alkynylsulfonyl
group, lower alkylaminocarbonyl group, lower alkenylaminocarbonyl group
or lower alkynylaminocarbonyl group may have one or a plurality of groups
selected from a halogen atom, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a hydroxy group, an ester of a hydroxy group, a lower
alkoxy group, a lower alkoxy group substituted with a halogen atom, a
lower alkylthio group, an amino group, a lower alkylamino group, an amide
of an amino group, an amide of a lower alkylamino group, a lower
alkylcarbonyl group, a carboxy group, an ester of a carboxy group, an
amide of a carboxy group, a lower alkylsulfonyl group, a nitro group and
a cyano group as substituents;

[0153]in the case where R8 or R9 is a lower cycloalkyl group, an
aryl group, a heterocyclic group, a lower cycloalkylcarbonyl group, an
arylcarbonyl group, a heterocyclic carbonyl group, a lower
cycloalkyloxycarbonyl group, an aryloxycarbonyl group, a heterocyclic
oxycarbonyl group, a lower cycloalkylsulfonyl group, an arylsulfonyl
group, a heterocyclic sulfonyl group, a lower cycloalkylaminocarbonyl
group, an arylaminocarbonyl group or a heterocyclic aminocarbonyl group,
the lower cycloalkyl group, aryl group, heterocyclic group, lower
cycloalkylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl
group, lower cycloalkyloxycarbonyl group, aryloxycarbonyl group,
heterocyclic oxycarbonyl group, lower cycloalkylsulfonyl group,
arylsulfonyl group, heterocyclic sulfonyl group, lower
cycloalkylaminocarbonyl group, arylaminocarbonyl group or heterocyclic
aminocarbonyl group may have one or a plurality of groups selected from a
halogen atom, a lower alkyl group, a lower alkyl group substituted with a
halogen atom, a lower alkyl group substituted with a hydroxy group, a
lower alkenyl group, a lower alkynyl group, a lower cycloalkyl group, an
aryl group, a heterocyclic group, a hydroxy group, an ester of a hydroxy
group, a lower alkoxy group, a lower alkoxy group substituted with a
halogen atom, a lower alkenyloxy group, a lower alkynyloxy group, a lower
alkylthio group, an amino group, a lower alkylamino group, an amide of an
amino group, an amide of a lower alkylamino group, a lower alkylcarbonyl
group, a carboxy group, an ester of a carboxy group, an amide of a
carboxy group, a lower alkylsulfonyl group, a nitro group and a cyano
group as substituents;

[0154]in the case where R7 is NR8R9, R8 and R9
may be combined together to form a 5- or 6-membered nitrogen-containing
heterocyclic ring; and/or

[0155](b9) X represents O.

[0156]That is, in the compounds represented by the general formula (1),
more preferred examples include compounds that comprises one or a
combination of two or more selected from the above (b1), (b2), (b3),
(b4), (b5), (b6), (b7), (b8) and (b9), and salts thereof.

[0157](c) Further more preferred examples of the present compound include
compounds in which the respective groups are groups as defined below and
salts thereof in the compounds represented by the general formula (1) and
salts thereof.

[0158]In the general formula (1),

[0159](c1) R1 represents a halogen atom, a lower alkyl group, a
hydroxy group, an ester of a hydroxy group, a lower alkoxy group, a lower
alkylthio group, an amino group, an amide of an amino group, an amide of
a lower alkylamino group, a lower alkylcarbonyl group, a carboxy group,
an ester of a carboxy group, a nitro group or a cyano group;

[0160]in the case where R1 is a lower alkyl group or a lower alkoxy
group, the lower alkyl group or lower alkoxy group may have one or a
plurality of groups selected from a halogen atom, a hydroxy group and a
lower alkoxy group as substituents; and/or

[0161](c2) p represents 1, 2 or 3;

[0162]in the case where p is 2 or 3, each R1 may be the same or
different; and/or

[0163](c3) q represents 0; and/or

[0164](c4) R3 represents a hydrogen atom; and/or

[0165](c5) R4 and R5 may be the same or different and represent
a lower alkyl group; and/or

[0166](c6) R6 represents a hydrogen atom, a lower alkyl group or a
lower alkenyl group; and/or

[0167](c7) A represents a lower alkylene group; and/or

[0168](c8) R7 represents OR8 or NR8R9;

[0169]R8 and R9 may be the same or different and represent a
hydrogen atom, an aryl group, an arylcarbonyl group or a heterocyclic
carbonyl group;

[0170]in the case where R8 or R9 is an aryl group, an
arylcarbonyl group or a heterocyclic carbonyl group, the aryl group,
arylcarbonyl group or heterocyclic carbonyl group may have one or a
plurality of groups selected from a halogen atom, a lower alkyl group, a
lower alkyl group substituted with at least a halogen atom, a lower alkyl
group substituted with at least a hydroxy group, a lower alkenyl group,
an aryl group, a lower alkoxy group, a lower alkylcarbonyl group, an
ester of a carboxy group, a nitro group and a cyano group as
substituents; and/or

[0171](c9) X represents O.

[0172]That is, in the compounds represented by the general formula (1),
further more preferred examples include compounds that comprises one or a
combination of two or more selected from the above (c1), (c2), (c3),
(c4), (c5), (c6), (c7), (c8) and (c9), and salts thereof.

[0173](d) Further more preferred examples of the present compound include
compounds in which the respective groups are groups as defined below and
salts thereof in the compounds represented by the general formula (1) and
salts thereof.

[0174]In the general formula (1),

[0175](d1) R1 represents a halogen atom, a hydroxy group, an ester of
a hydroxy group, a lower alkoxy group, an amide of an amino group or an
amide of a lower alkylamino group; and/or

[0176](d2) p represents 2 or 3, in this case, each R1 may be the same
or different; and/or

[0177](d3) q represents 0; and/or

[0178](d4) R3 represents a hydrogen atom; and/or

[0179](d5) R4 and R5 may be the same or different and represent
a lower alkyl group; and/or

[0180](d6) R6 represents a lower alkyl group; and/or

[0181](d7) A represents a lower alkylene group; and/or

[0182](d8) R7 represents OR8 or NR8R9;

[0183]R8 represents an aryl group, an arylcarbonyl group or a
heterocyclic carbonyl group, in this case, the aryl group, arylcarbonyl
group or heterocyclic carbonyl group may have one or a plurality of
groups selected from a halogen atom, a lower alkyl group, a lower alkyl
group substituted with at least a halogen atom, a lower alkyl group
substituted with at least a hydroxy group, a lower alkenyl group, an aryl
group, a lower alkoxy group, a lower alkylcarbonyl group, an ester of a
carboxy group, a nitro group and a cyano group as substituents;

[0184]R9 represents a hydrogen atom; and/or

[0185](d9) X represents O.

[0186]That is, in the compounds represented by the general formula (1),
further more preferred examples include compounds that comprises one or a
combination of two or more selected from the above (d1), (d2), (d3),
(d4), (d5), (d6), (d7), (d8) and (d9), and salts thereof.

[0187](e) Preferred examples of R1 in the present compound include
compounds that satisfy the following requirement and salts thereof.

[0188]A compound or a salt thereof wherein in the general formula (1),
R1 represents a halogen atom, a hydroxy group, an ester of a hydroxy
group, a lower alkoxy group, an amide of an amino group or an amide of a
lower alkylamino group, and satisfies the requirement of the above (a),
(b) and/or (c).

[0189](f) Preferred examples of R4, R5 and R6 in the
present compound include compounds that satisfy the following requirement
and salts thereof.

[0190]A compound or a salt thereof wherein in the general formula (1),
R4, R5 and R6 each represent a methyl group, and satisfies
the requirement of the above (a), (b), (c) and/or (d).

[0191](g) Preferred examples of R8 in the present compound include
compounds that satisfy the following requirement and salts thereof.

[0192]A compound or a salt thereof wherein in the general formula (1),
R8 represents an aryl group, an arylcarbonyl group or a heterocyclic
carbonyl group, and the aryl group represents a phenyl group, the
arylcarbonyl group represents a phenylcarbonyl group, and/or the
heterocyclic carbonyl group represents a thiophenecarbonyl group, and
satisfies the requirement of the above (a), (b), (c) and/or (d).

[0193](h) Preferred examples of A in the present compound include
compounds that satisfy the following requirement and salts thereof.

[0194]A compound or a salt thereof wherein in the general formula (1), A
represent a methylene group, and satisfies the requirement of the above
(a), (b), (c) and/or (d).

[0195](i) Preferred examples of which R1 is an ester of a hydroxyl
group in the present compound include compounds that satisfy the
following requirement and salts thereof.

[0196]In the R1 of the general formula (1), the ester of a hydroxy
group represents --OCO--Ra1, in which the Ra1 represents a
hydrogen atom, a lower alkyl group which may have at least a substituent,
a lower alkenyl group which may have at least a substituent, a lower
alkynyl group which may have at least a substituent, a lower cycloalkyl
group which may have at least a substituent, an aryl group which may have
at least a substituent, a heterocyclic group which may have at least a
substituent, a lower alkoxy group which may have at least a substituent,
a lower alkenyloxy group which may have at least a substituent, a lower
alkynyloxy group which may have at least a substituent, a lower
cycloalkyloxy group which may have at least a substituent, an aryloxy
group which may have at least a substituent, a heterocyclic oxy group
which may have at least a substituent, an amino group, a lower alkylamino
group which may have at least a substituent, a lower cycloalkylamino
group which may have at least a substituent, an arylamino group which may
have at least a substituent or a heterocyclic amino group which may have
at least a substituent,

[0198]in the case where Ra1 is a lower alkyl group, a lower alkenyl
group, a lower alkoxy group, a lower alkenyloxy group or a lower
alkylamino group, the lower alkyl group, lower alkenyl group, lower
alkoxy group, lower alkenyloxy group or lower alkylamino group may have
one or a plurality of groups selected from a halogen atom, an aryl group,
a heterocyclic group, a hydroxy group, an ester of a hydroxy group, an
amino group, a lower alkylamino group, a carboxy group and an ester of a
carboxy group as substituents; and

[0199]in the case where Ra1 is a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower cycloalkyloxy group, an aryloxy
group, a heterocyclic oxy group, a lower cycloalkylamino group, an
arylamino group or a heterocyclic amino group, the lower cycloalkyl
group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy
group, heterocyclic oxy group, lower cycloalkylamino group, arylamino
group or heterocyclic amino group may have one or a plurality of groups
selected from a halogen atom, a lower alkyl group, a lower alkyl group
substituted with at least a halogen atom, a hydroxy group, an ester of a
hydroxy group, a lower alkoxy group, a mercapto group, a lower alkylthio
group, a formyl group, a lower alkylcarbonyl group, a carboxy group, an
ester of a carboxy group, a nitro group and a cyano group as
substituents,

[0200]further more preferred examples, the Ra1 represents a lower
alkyl group, a lower alkenyl group, a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower alkoxy group, an aryloxy group, a
lower alkylamino group, a lower cycloalkylamino group, an arylamino group
or a heterocyclic amino group;

[0201]in the case where Ra1 is a lower alkyl group, the lower alkyl
group may have one or a plurality of groups selected from an aryl group
and a lower alkylamino group as substituents;

[0202]in the case where Ra1 is an aryl group, the aryl group may have
one or a plurality of groups selected from a halogen atom, a lower alkyl
group, a lower alkyl group substituted with at least a halogen atom, an
ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group,
a lower alkylcarbonyl group, an ester of a carboxy group and a nitro
group as substituents;

[0203]in the case where Ra1 is a heterocyclic group, the heterocyclic
group may have one or a plurality of groups selected from a halogen atom,
a lower alkyl group, a hydroxy group and a lower alkoxy group as
substituents;

[0204]in the case where Ra1 is a lower alkylamino group, the lower
alkylamino group may have one or a plurality of groups selected from an
aryl group, a heterocyclic group and an ester of a carboxy group as
substituents; and

[0205]in the case where Ra1 is an arylamino group, the arylamino
group may have one or a plurality of groups selected from a halogen atom,
a lower alkyl group and a lower alkoxy group as substituents, and
satisfies the requirement of the above (a), (b), (c) (d) and/or (e).

[0206](j) Preferred examples of which R1 is an amide of an amino
group in the present compound include compounds that satisfy the
following requirement and salts thereof.

[0207]In the R1 of the general formula (1), the amide of an amino
group represents --NHCO--Rb, in which the Rb1 represents a
hydrogen atom, a lower alkyl group which may have at least a substituent,
a lower alkenyl group which may have at least a substituent, a lower
alkynyl group which may have at least a substituent, a lower cycloalkyl
group which may have at least a substituent, an aryl group which may have
at least a substituent, a heterocyclic group which may have at least a
substituent, a lower alkoxy group which may have at least a substituent,
a lower alkenyloxy group which may have at least a substituent, a lower
alkynyloxy group which may have at least a substituent, a lower
cycloalkyloxy group which may have at least a substituent, an aryloxy
group which may have at least a substituent, a heterocyclic oxy group
which may have at least a substituent, an amino group, a lower alkylamino
group which may have at least a substituent, a lower cycloalkylamino
group which may have at least a substituent, an arylamino group which may
have at least a substituent or a heterocyclic amino group which may have
at least a substituent, more preferred examples, Rb1 represents a
hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower
cycloalkyl group, an aryl group, a heterocyclic group, a lower alkoxy
group, a lower alkenyloxy group, a lower cycloalkyloxy group, an aryloxy
group, a heterocyclic oxy group, an amino group, a lower alkylamino
group, a lower cycloalkylamino group, an arylamino group or a
heterocyclic amino group;

[0208]in the case where Rb1 is a lower alkyl group, a lower alkenyl
group, a lower alkoxy group, a lower alkenyloxy group or a lower
alkylamino group, the lower alkyl group, lower alkenyl group, lower
alkoxy group, lower alkenyloxy group or lower alkylamino group may have
one or a plurality of groups selected from a halogen atom, an aryl group,
a heterocyclic group, a hydroxy group, an ester of a hydroxy group, an
amino group, a lower alkylamino group, a carboxy group and an ester of a
carboxy group as substituents; and

[0209]in the case where Rb1 is a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower cycloalkyloxy group, an aryloxy
group, a heterocyclic oxy group, a lower cycloalkylamino group, an
arylamino group or a heterocyclic amino group, the lower cycloalkyl
group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy
group, heterocyclic oxy group, lower cycloalkylamino group, arylamino
group or heterocyclic amino group may have one or a plurality of groups
selected from a halogen atom, a lower alkyl group, a lower alkyl group
substituted with at least a halogen atom, a hydroxy group, an ester of a
hydroxy group, a lower alkoxy group, a mercapto group, a lower alkylthio
group, a formyl group, a lower alkylcarbonyl group, a carboxy group, an
ester of a carboxy group, a nitro group and a cyano group as
substituents,

[0210]further more preferred examples, the Rb1 represents a lower
alkyl group, an aryl group, a heterocyclic group, an aryloxy group, a
lower alkylamino group or an arylamino group;

[0211]in the case where Rb1 is a lower alkyl group, the lower alkyl
group may have one or a plurality of amino groups as substituents;

[0212]in the case where Rb1 is an aryl group, the aryl group may have
one or a plurality of groups selected from a halogen atom, a lower alkyl
group, a lower alkyl group substituted with at least a halogen atom, an
ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group,
a lower alkylcarbonyl group, an ester of a carboxy group and a nitro
group as substituents;

[0213]in the case where Rb1 is a heterocyclic group, the heterocyclic
group may have one or a plurality of groups selected from a halogen atom,
a lower alkyl group, a hydroxy group and a lower alkoxy group as
substituents; and

[0214]in the case where Rb1 is a lower alkylamino group, the lower
alkylamino group may have one or a plurality of aryl groups as
substituents, and satisfies the requirement of the above (a), (b), (c)
(d) and/or (e).

[0215](k) Preferred examples of which R1 is an amide of a lower
alkylamino group in the present compound include compounds that satisfy
the following requirement and salts thereof.

[0216]In the R1 of the general formula (1), the amide of a lower
alkylamino group represents --NRc1CO--Rc2, in which the
Rc1 represents a lower alkyl group which may have at least a
substituent, and the Rc2 represents a hydrogen atom, a lower alkyl
group which may have at least a substituent, a lower alkenyl group which
may have at least a substituent, a lower alkynyl group which may have at
least a substituent, a lower cycloalkyl group which may have at least a
substituent, an aryl group which may have at least a substituent, a
heterocyclic group which may have at least a substituent, a lower alkoxy
group which may have at least a substituent, a lower alkenyloxy group
which may have at least a substituent, a lower alkynyloxy group which may
have at least a substituent, a lower cycloalkyloxy group which may have
at least a substituent, an aryloxy group which may have at least a
substituent, a heterocyclic oxy group which may have at least a
substituent, an amino group, a lower alkylamino group which may have at
least a substituent, a lower cycloalkylamino group which may have at
least a substituent, an arylamino group which may have at least a
substituent or a heterocyclic amino group which may have at least a
substituent,

[0217]more preferred examples, the Rc1 represents a lower alkyl
group, and the Rc2 represents a hydrogen atom, a lower alkyl group,
a lower alkenyl group, a lower cycloalkyl group, an aryl group, a
heterocyclic group, a lower alkoxy group, a lower alkenyloxy group, a
lower cycloalkyloxy group, an aryloxy group, a heterocyclic oxy group, an
amino group, a lower alkylamino group, a lower cycloalkylamino group, an
arylamino group or a heterocyclic amino group;

[0218]in the case where Rc2 is a lower alkyl group, a lower alkenyl
group, a lower alkoxy group, a lower alkenyloxy group or a lower
alkylamino group, the lower alkyl group, lower alkenyl group, lower
alkoxy group, lower alkenyloxy group or lower alkylamino group may have
one or a plurality of groups selected from a halogen atom, an aryl group,
a heterocyclic group, a hydroxy group, an ester of a hydroxy group, an
amino group, a lower alkylamino group, a carboxy group and an ester of a
carboxy group as substituents; and

[0219]in the case where Rc2 is a lower cycloalkyl group, an aryl
group, a heterocyclic group, a lower cycloalkyloxy group, an aryloxy
group, a heterocyclic oxy group, a lower cycloalkylamino group, an
arylamino group or a heterocyclic amino group, the lower cycloalkyl
group, aryl group, heterocyclic group, lower cycloalkyloxy group, aryloxy
group, heterocyclic oxy group, lower cycloalkylamino group, arylamino
group or heterocyclic amino group may have one or a plurality of groups
selected from a halogen atom, a lower alkyl group, a lower alkyl group
substituted with at least a halogen atom, a hydroxy group, an ester of a
hydroxy group, a lower alkoxy group, a mercapto group, a lower alkylthio
group, a formyl group, a lower alkylcarbonyl group, a carboxy group, an
ester of a carboxy group, a nitro group and a cyano group as
substituents,

[0220]further more preferred examples, the Rc represents a lower
alkyl group, and the Rc2 represents, a lower alkyl group, an aryl
group or a heterocyclic group;

[0221]in the case where Rc2 is a lower alkyl group, the lower alkyl
group may have one or a plurality of amino groups as substituents;

[0222]in the case where Rc2 is an aryl group, the aryl group may have
one or a plurality of groups selected from a halogen atom, a lower alkyl
group, a lower alkyl group substituted with at least a halogen atom, an
ester of a hydroxy group, a lower alkoxy group, a lower alkylthio group,
a lower alkylcarbonyl group, an ester of a carboxy group and a nitro
group as substituents;

[0223]in the case where Rc2 is a heterocyclic group, the heterocyclic
group may have one or a plurality of groups selected from a halogen atom,
a lower alkyl group, a hydroxy group and a lower alkoxy group as
substituents; and

[0224]in the case where Rc2 is a lower alkylamino group, the lower
alkylamino group may have one or a plurality of aryl groups as
substituents, and satisfies the requirement of the above (a), (b), (c)
(d) and/or (e).

[0306]The present compound can be synthesized according to the following
procedures. The individual concrete preparation procedures are explained
in details in the following examples, [preparation examples]. These
examples are intended to make the present invention more clearly
understandable, and do not limit the scope of the present invention. The
Hal shown in the following synthetic routes represents a halogen atom,
MOM represents methoxymethyl group and Fmoc represents
9-fluorenylmethoxycarbonyl group.

[0307]The present compound (I)-(a) (the compound that A is methylene
group, X is O in the general formula (1)) can be synthesized according to
the synthetic route 1. Namely, the compound (I)-(a) can be given by the
reaction of the present compound (I)-(b) (the compound that A is
methylene group, X is O, R6 is H in the general formula (1)) with a
corresponding halide (II) in an organic solvent such as
N,N-dimethylformamide (hereinafter referred to as DMF), tetrahydrofuran
(hereinafter referred to as THF), 1,4-dioxane, methylene dichloride in
the presence of a base such as cesium carbonate, potassium carbonate at
0° C. to 50° C. for 1 hour to 24 hours.

##STR00003##

[0308]The present compound (I)-(b) (the compound that A is methylene
group, X is O, R6 is H, R7 is OR8, NR8R9 or
SR8 in the general formula (1)) can be synthesized according to the
synthetic route 2. Namely, the compound (I)-(b) can be given by the
reaction of the compound (III) with a corresponding alcohol, carboxylic
acid, phenol, amine, thiol, thiophenol and the like (IV) in an organic
solvent such as DMF, THF, ethanol in the presence of a base such as
potassium carbonate, sodium hydride at 0° C. to 100° C. for
1 hour to 48 hours.

##STR00004##

[0309]The present compound (I)-(c) (the compound that A is methylene
group, X is O, R7 is OR8 in the general formula (1)) can be
synthesized according to the synthetic route 3. Namely, the compound
(I)-(c) can be given by the reaction of the compound (V) with a
corresponding halide (VI) in an organic solvent such as DMF, THF,
methylene dichloride in the presence of a base such as triethylamine,
potassium carbonate at 0° C. to 50° C. for 1 hour to 48
hours.

##STR00005##

[0310]The compound (III) and (V) can be synthesized according to the
synthetic route 4. Namely, the compound (IX) can be given by the reaction
of the compound (VII) with a corresponding boronic acid or its ester
(VIII) in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water and
in the presence of a base such as cesium carbonate, sodium carbonate,
sodium hydrogen carbonate, tripotassium phosphate and a catalyst such as
bis(triphenylphosphine)palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0) at 50° C. to 120°
C. for 1 hour to 48 hours. The compound (V) can be given by the treatment
of the compound (IX) in an organic solvent such as diethylether, THF in
the presence of a reductive agent such as lithium aluminium hydride at
-30° C. to room temperature for 1 hour to 24 hours. The compound
(III) can be given by the treatment of the compound (V) with
methanesulfonyl chloride in an organic solvent such as methylene
dichloride, THF in the presence of a base such as triethylamine,
diisopropylethylamine (hereinafter referred to as DIEA) at 0° C.
to room temperature for 30 minutes to 12 hours.

##STR00006##

[0311]The compound (VII) can be synthesized according to the synthetic
route 5. Namely, the compound (XI) can be given by the treatment of the
compound (X) in an organic solvent such as methanol, ethanol, DMF in the
presence of a reductive agent such as tin(II) chloride, ferric(II)
chloride at 50° C. to 120° C. for 1 hour to 12 hours. The
compound (XII) can be given by the treatment of the compound (XI) with an
acetylation agent such as acetyl chloride, acetic anhydride in an organic
solvent such as methylene dichloride, THF in the presence of a base such
as triethylamine, DIEA at 0° C. to 50° C. for 1 hour to 12
hours. The compound (XIII) can be given by the treatment of the compound
(XII) with nitric acid in a solvent such as water in the presence of an
acid such as sulfuric acid at -20° C. to room temperature for 30
minutes to 12 hours. The compound (XIV) can be given by the treatment of
the compound (XIII) in an organic solvent such as methanol in the
presence of an acid such as boron trifluoride ether complex at 50°
C. to the temperature under reflux for 1 hour to 12 hours.

[0312]The compound (XVI) can be given by the reaction of the compound
(XIV) with a corresponding halide (XV) in the presence of a base such as
cesium carbonate, potassium carbonate at 50° C. to 120° C.
for 1 hour to 120 hours. The compound (VII) can be given by the treatment
of the compound (XVI) in an organic solvent such as methanol, ethanol,
DMF in the presence of a reductive agent such as tin(II) chloride,
ferric(II) chloride at 50° C. to 120° C. for 1 hour to 12
hours.

##STR00007## ##STR00008##

[0313]The present compound (I)-(a) (the compound that A is methylene
group, X is O in the general formula (1)) can be also synthesized
according to the synthetic route 6. Namely, the compound (I)-(a) can be
given by the reaction of the compound (XVII) with a corresponding boronic
acid or its ester (VIII) in a solvent such as DMF, 1,4-dioxane, ethanol,
toluene, water and in the presence of a base such as cesium carbonate,
sodium carbonate, sodium hydrogen carbonate, tripotassium phosphate and a
catalyst such as bis(triphenylphosphine)palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0) at 50° C. to 120°
C. for 1 hour to 48 hours.

##STR00009##

[0314]Moreover, the present compound (I)-(a) (the compound that A is
methylene group, X is O in the general formula (1)) can be also
synthesized according to the synthetic route 7. Namely, the compound
(I)-(a) can be given by the reaction of the compound (XVIII) with a
corresponding halide (XIX) in a solvent such as DMF, 1,4-dioxane,
ethanol, toluene, water and in the presence of a base such as cesium
carbonate, sodium carbonate, sodium hydrogen carbonate, tripotassium
phosphate and a catalyst such as bis(triphenylphosphine)palladium (II)
dichloride, tetrakis(triphenylphosphine)palladium (0) at 50° C. to
120° C. for 1 hour to 48 hours.

##STR00010##

[0315]The compound (XVII) and (XVIII) can be synthesized according to the
synthetic route 8. Namely, the compound (XX) can be given by the
treatment of the compound (VII) in an organic solvent such as
diethylether, THF in the presence of a reductive agent such as lithium
aluminium hydride at 0° C. to 50° C. for 1 hour to 24
hours. The compound (XXI) can be given by the reaction of the compound
(XX) with a corresponding halide (II) in an organic solvent such as DMF,
THF, 1,4-dioxane, methylene dichloride in the presence of a base such as
cesium carbonate, potassium carbonate at 0° C. to 50° C.
for 1 hour to 24 hours. The compound (XXII) can be given by the treatment
of the compound (XXI) with methanesulfonyl chloride in an organic solvent
such as methylene dichloride, THF in the presence of a base such as
triethylamine, DIEA at 0° C. to room temperature for 30 minutes to
12 hours. The compound (XVII) can be given by the reaction of the
compound (XXII) with a corresponding alcohol, carboxylic acid, phenol,
amine, thiol, thiophenol (IV) in an organic solvent such as DMF, THF,
ethanol in the presence of a base such as potassium carbonate, sodium
hydride at 0° C. to 100° C. for 1 hour to 48 hours. The
compound (XVIII) can be given by the reaction of the compound (XVII) with
a corresponding diboron (XXIII) or borane (XXIV) in a solvent such as
dimethylsulfoxide, DMF, 1,4-dioxane in the presence of a base such as
potassium acetate, triethylamine and a catalyst such as
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride,
bis(triphenylphosphine)palladium (II) dichloride at 50° C. to
120° C. for 10 minutes to 48 hours.

##STR00011##

[0316]The present compound (I)-(d) (the compound that A is methylene
group, X is O, one of R1 is OR10, R10 is a lower alkyl
group which may have at least a substituent, a lower alkylcarbonyl group
which may have at least a substituent, an arylcarbonyl group which may
have at least a substituent, a heterocyclic carbonyl group which may have
at least a substituent, a lower alkoxycarbonyl group which may have at
least a substituent or an aryloxycarbonyl group which may have at least a
substituent, and the like in the general formula (1)) can be synthesized
according to the synthetic route 9. Namely, the compound (I)-(d) can be
given by the reaction of the present compound (I)-(e) (the compound that
A is methylene group, X is O, one of R1 is OH in the general formula
(1)) with a corresponding halide (XXV) in an organic solvent such as THF,
methylene dichloride, DMF in the presence of a base such as
triethylamine, DIEA, potassium carbonate at 0° C. to 100°
C. for 1 hour to 24 hours.

##STR00012##

[0317]The present compound (I)-(f) (the compound that A is methylene
group, X is O, one of the R1 is OCOR11, R11 is a lower
alkyl group which may have at least a substituent, an aryl group which
may have at least a substituent or a heterocyclic group which may have at
least a substituent, and the like in the general formula (1)) can be
synthesized according to the synthetic route 10. Namely, the compound
(I)-(f) can be given by the reaction of the present compound (I)-(e) (the
compound that A is methylene group, X is O, one of R1 is OH in the
general formula (1)) with a corresponding carboxylic acid (XXVI) in an
organic solvent such as DMF, methylene dichloride in the presence of a
condensation agent such as N,N'-dicyclohexylcarbodiimide (hereinafter
referred to as DCC), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyl
uroniumhexafluorophosphate (hereinafter referred to as HATU) and a base
such as DIEA at room temperature to 50° C. for 1 hour to 3 days.

##STR00013##

[0318]The present compound (I)-(g) (the compound that A is methylene
group, X is O, one of the R1 is OCONR12R13, R12 and
R13 may be the same or different and are a lower alkyl group which
may have at least a substituent, an aryl group which may have at least a
substituent, and the like in the general formula (1)) can be synthesized
according to the synthetic route 11. Namely, the compound (I)-(g) can be
given by the reaction of the present compound (I)-(e) (the compound that
A is methylene group, X is O, one of the R1 is OH in the general
formula (1)) with 1,1'-carbonyldiimidazole (hereinafter referred to as
CDI) in an organic solvent such as methylene dichloride, THF at room
temperature to 50° C. for 30 minutes to 12 hours followed by the
reaction with a corresponding amine (XXVII).

##STR00014##

[0319]The present compound (I)-(e) (the compound that A is methylene
group, X is O, one of the R1 is OH in the general formula (1)) can
be synthesized according to the synthetic route 12. Namely, the present
compound (I)-(h) can be given by the reaction of the compound (XVII) with
a corresponding boronic acid or its ester (XXVIII) in a solvent such as
DMF, 1,4-dioxane, ethanol, toluene, water in the presence of a base such
as cesium carbonate, sodium carbonate, sodium hydrogen carbonate,
tripotassium phosphate and a catalyst such as
bis(triphenylphosphine)palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0) at 50° C. to 120°
C. for 1 hour to 48 hours. The compound (I)-(e) can be given by the
treatment of the compound (I)-(h) in an organic solvent such as
1,4-dioxane, methylene dichloride in the presence of an acid such as
hydrogen chloride, trifluoroacetic acid at 0° C. to 50° C.
for 1 hour to 24 hours.

##STR00015##

[0320]Further, the present compound (I)-(e) (the compound that A is
methylene group, X is O, one of the R1 is OH in the general formula
(1)) can be also synthesized according to the synthetic route 13. Namely,
the compound (XXIX) can be given by the reaction of the compound (VII)
with a corresponding boronic acid or its ester (XXVIII) in a solvent such
as DMF, 1,4-dioxane, ethanol, toluene, water in the presence of a base
such as cesium carbonate, sodium carbonate, sodium hydrogen carbonate,
tripotassium phosphate and a catalyst such as
bis(triphenylphosphine)palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0) at 50° C. to 120°
C. for 1 hour to 48 hours. The compound (XXX) can be given by the
treatment of the compound (XXIX) in an organic solvent such as
diethylether, THF in the presence of a reductive agent such as lithium
aluminium hydride at -30° C. to room temperature for 1 hour to 24
hours. The compound (XXXI) can be given by the treatment of the compound
(XXX) with methanesulfonyl chloride in an organic solvent such as
methylene dichloride, THF in the presence of a base such as
triethylamine, DIEA at 0° C. to room temperature for 30 minutes to
12 hours. The present compound (I)-(i) can be given by the reaction of
the compound (XXXI) with a corresponding alcohol, carboxylic acid,
phenol, amine, thiol, thiophenol and the like (IV) in an organic solvent
such as DMF, THF, ethanol in the presence of a base such as potassium
carbonate, sodium hydride at 0° C. to 100° C. for 1 hour to
48 hours. The present compound (I)-(h) can be given by the reaction of
the compound (I)-(i) with a corresponding halide (II) in an organic
solvent such as DMF, THF, 1,4-dioxane, methylene dichloride in the
presence of a base such as cesium carbonate, potassium carbonate at
0° C. to 50° C. for 1 hour to 24 hours. The compound
(I)-(e) can be given by the treatment of the compound (I)-(h) in an
organic solvent such as 1,4-dioxane, methylene dichloride in the presence
of an acid such as hydrogen chloride, trifluoroacetic acid at 0°
C. to 50° C. for 1 hour to 24 hours.

##STR00016## ##STR00017##

[0321]The present compound (I)-(j) (the compound that A is methylene
group, X is O, one of the R1 is OR10, R7 is NHR8,
R10 is a lower alkyl group which may have at least a substituent, a
lower alkylcarbonyl group which may have at least a substituent, an
arylcarbonyl group which may have at least a substituent, a heterocyclic
carbonyl group which may have at least a substituent, a lower
alkoxycarbonyl group which may have at least a substituent, an
aryloxycarbonyl group which may have at least a substituent, and the like
in the general formula (1)), the present compound (I)-(k) (the compound
that A is methylene group, X is O, one of the R1 is OCOR11,
R7 is NHR8, R1'' is a lower alkyl group which may have at
least a substituent, an aryl group which may have at least a substituent,
a heterocyclic group which may have at least a substituent, and the like
in the general formula (1)) and the present compound (I)-(l) (the
compound that A is methylene group, X is O, one of the R1 is
OCONR12R13, R7 is NHR8, R12 and R13 may be
the same or different and are a lower alkyl group which may have at least
a substituent, an aryl group which may have at least a substituent, and
the like in the general formula (1)) can be synthesized according to the
synthetic route 14. Namely, the compound (I)-(j), (I)-(k) and (I)-(l) can
be given by the reaction of the present compound (I)-(m) (the compound
that A is methylene group, X is O, one of the R1 is OH, R7 is
NR8(Fmoc) in the general formula (1)) with a corresponding halide
(XXV), a carboxylic acid (XXVI) or an amine (XXVII) according to the
method of synthetic route 9, 10 or 11 respectively, followed by the
treatment in an organic solvent such as DMF, methylene dichloride in the
presence of a base such as piperidine at 0° C. to 50° C.
for 5 minutes to 24 hours.

##STR00018##

[0322]The present compound (I)-(m) (the compound that A is methylene
group, X is O, one of the R1 is OH, R7 is NR8(Fmoc) in the
general formula (1)) can be synthesized according to the synthetic route
15. Namely, the compound (XXXIII) can be given by the reaction of the
compound (XXII) with a corresponding amine (XXXII) in an organic solvent
such as DMF, THF, ethanol in the presence of a base such as potassium
carbonate, sodium hydride at 0° C. to 100° C. for 1 hour to
48 hours. The present compound (I)-(o) can be given by the reaction of
the compound (XXXIII) with a corresponding boronic acid or its ester
(XXVIII) in a solvent such as DMF, 1,4-dioxane, ethanol, toluene, water
in the presence of a base such as cesium carbonate, sodium carbonate,
sodium hydrogen carbonate, tripotassium phosphate and a catalyst such as
bis(triphenylphosphine)palladium (II) dichloride,
tetrakis(triphenylphosphine)palladium (0) at 50° C. to 120°
C. for 1 hour to 48 hours. The present compound (I)-(n) can be given by
the reaction of the compound (I)-(o) with 9-fluorenylmethoxycarbonyl
chloride in a solvent such as 1,4-dioxane, water in the presence of a
base such as sodium hydrogen carbonate at 0° C. to 50° C.
for 1 hour to 24 hours. The compound (I)-(m) can be given by the
treatment of the compound (I)-(n) in an organic solvent such as
1,4-dioxane, methylene dichloride in the presence of an acid such as
hydrogen chloride, trifluoroacetic acid at 0° C. to 50° C.
for 1 hour to 24 hours.

##STR00019##

[0323]The present compound (I)-(p) (the compound that A is methylene
group, X is O, one of the R1 is OR10, R7 is OR8,
R10 is a lower alkyl group which may have at least a substituent, a
lower alkylcarbonyl group which may have at least a substituent, an
arylcarbonyl group which may have at least a substituent, a heterocyclic
carbonyl group which may have at least a substituent, a lower
alkoxycarbonyl group which may have at least a substituent, an
aryloxycarbonyl group which may have at least a substituent, and the like
in the general formula (1)) can be synthesized according to the synthetic
route 16. Namely, the compound (XXXIV) can be given by the treatment of
the compound (XXX) in an organic solvent such as 1,4-dioxane, methylene
dichloride in the presence of an acid such as hydrogen chloride,
trifluoroacetic acid at 0° C. to 50° C. for 1 hour to 24
hours. The compound (XXXV) can be given by the reaction of the compound
(XXXIV) with a corresponding halide (XXV) in an organic solvent such as
THF, methylene dichloride, DMF in the presence of a base such as
triethylamine, DIEA, potassium carbonate at 0° C. to 100°
C. for 1 hour to 24 hours. The compound (I)-(q) can be given by the
reaction of the compound (XXXV) with a corresponding halide (VI) in an
organic solvent such as DMF, THF, methylene dichloride in the presence of
a base such as triethylamine, potassium carbonate at 0° C. to
50° C. for 1 hour to 48 hours. The compound (I)-(p) can be given
by the reaction of the compound (I)-(q) with a corresponding halide (II)
in an organic solvent such as DMF, THF, 1,4-dioxane, methylene dichloride
in the presence of a base such as cesium carbonate, potassium carbonate
at 0° C. to 50° C. for 1 hour to 24 hours.

##STR00020##

[0324]The present invention also relates to a method of preventing or
treating a glucocorticoid receptor-related disease, for example,
metabolic disorders such as diabetes and obesity, inflammatory diseases
such as arthritis, enteritis and chronic obstructive pulmonary diseases,
autoimmune diseases such as connective tissue diseases, allergic diseases
such as asthma, atopic dermatitis, allergic rhinitis and conjunctivitis,
central nervous system diseases such as psychiatric disorders,
Alzheimer's disease and drug use disorders, cardiovascular diseases such
as hypertension, hypercalcemia, hyperinsulinemia and hyperlipidemia,
homeostasis-related diseases causing an abnormality of
neuro-immune-endocrine balance, glaucoma, comprising administering to a
patient a therapeutically effective amount of the present compound or a
salt thereof.

[0325]In order to find the usefulness of the present compound as a
pharmaceutical, by using a glucocorticoid receptor competitor assay kit,
a glucocorticoid receptor competitor assay was carried out by a
fluorescence polarization method. As a result, the present compound
showed an excellent glucocorticoid receptor binding activity.
Incidentally, the glucocorticoid receptor is associated with the
occurrence of various diseases as described above, therefore, the present
compound having an excellent binding activity to the glucocorticoid
receptor is useful as a glucocorticoid receptor modulator.

[0326]A detailed explanation of this matter will be described in the
section of "Pharmacological Test" in Examples described below.

[0327]The present compound can be administered either orally or
parenterally. Examples of the dosage form include a tablet, a capsule, a
granule, a powder, an injection, an eye drop and the like. Such a
preparation can be prepared using a commonly used technique.

[0328]For example, an oral preparation such as a tablet, a capsule, a
granule or a powder can be prepared by optionally adding a necessary
amount of an excipient such as lactose, mannitol, starch, crystalline
cellulose, light silicic anhydride, calcium carbonate or calcium hydrogen
phosphate; a lubricant such as stearic acid, magnesium stearate or talc;
a binder such as starch, hydroxypropyl cellulose, hydroxypropylmethyl
cellulose or polyvinylpyrrolidone; a disintegrant such as carboxymethyl
cellulose, low-substituted hydroxypropylmethyl cellulose or calcium
citrate; a coating agent such as hydroxypropylmethyl cellulose, macrogol
or a silicone resin; a stabilizer such as ethyl p-hydroxybenzoate or
benzyl alcohol; a corrigent such as a sweetener, a sour agent or a
flavor, or the like.

[0329]A parenteral preparation such as an injection or an eye drop can be
prepared by optionally adding a necessary amount of a tonicity agent such
as sodium chloride, concentrated glycerin, propylene glycol, polyethylene
glycol, potassium chloride, sorbitol or mannitol; a buffer such as sodium
phosphate, sodium hydrogen phosphate, sodium acetate, citric acid,
glacial acetic acid or trometamol; a surfactant such as polyoxyethylene
sorbitan monoolate, polyoxy 40 stearate or polyoxyethylene hydrogenated
castor oil 60; a stabilizer such as sodium citrate or sodium edetate; a
preservative such as benzalkonium chloride, paraben, benzothonium
chloride, p-hydroxybenzoate ester, sodium benzoate or chlorobutanol; a pH
adjusting agent such as hydrochloric acid, citric acid, phosphoric acid,
glacial acetic acid, sodium hydroxide, sodium carbonate or sodium
hydrogen carbonate; a soothing agent such as benzyl alcohol, or the like.

[0330]The dose of the present compound can be appropriately selected
depending on the symptoms, age, dosage form or the like. For example, in
the case of an oral preparation, it can be administered in an amount of
generally 0.01 to 1000 mg, preferably 1 to 100 mg per day in a single
dose or several divided doses. Further, in the case of an eye drop, a
preparation containing the present compound at a concentration of
generally 0.0001% to 10% (w/v), preferably 0.01% to 5% (w/v) can be
administered in a single dose or several divided doses.

[0331]Hereinafter, Production Examples of the present compound,
Preparation Examples and results of Pharmacological Test will be
described. However, these examples are described for the purpose of
understanding the present invention better and are not meant to limit the
scope of the present invention.

[0332]Fmoc in the chemical structure in Production Examples represents
9-fluorenylmethoxycarbonyl group.

Using any compounds among Reference Compounds No. 1, 18-3, 18-5 and
available compounds, the following Reference Compounds (No.
2-2˜2-5) were obtained by a method similar to that of Reference
Compound No. 2-1.

Using any compounds among Reference Compounds No. 15-1 and available
compounds, the following Reference Compounds (No. 16-2˜16-3) were
obtained by a method similar to that of Reference Compound No. 16-1.

Using any compounds among Reference Compounds No. 15-2, 16-2, 23 and
available compounds, the following Reference Compounds (No.
18-2˜18-7) were obtained by a method similar to that of Reference
Compound No. 18-1.

Using any compounds among Reference Compounds No. 1-4˜1-7,
2-1˜2-6, 2-13, 3-1˜3-6, 4-1˜4-4, 22, and available
compounds, the following Compounds (No. 5-2˜5-25) were obtained by
a method similar to that of Compound No. 5-1.

Using any compounds among Reference Compounds No. 8-1˜8-4, 17,
18-1˜18-5, 20-1, 20-2, and available compounds, the following
Compounds (No. 6-2˜6-34 and 6-37˜6-43) were obtained by a
method similar to that of Compound No. 6-1. The following Compounds (No.
6-35 and 6-36) were obtained by a method similar to that of Reference
Compound No. 20-1 using any compounds among Reference Compounds No. 19-2,
19-3, and available compounds followed by a method similar to that of
Compound No. 6-1 using Reference Compound No. 8-1 and available
compounds.

Using any compounds among Compounds No. 13-1, 13-3, and available
compounds, the following Compounds (No. 21-2˜21-24) were obtained
by a method similar to that of Compound No. 14-1, 15-1, 17-1 or 18-1
followed by a method similar to that of Compound No. 21-1.

[0386]A tablet of the above-mentioned formulation is coated with 3 mg of a
coating agent (for example, a conventional coating agent such as
hydroxypropylmethyl cellulose, macrogol or a silicone resin), whereby an
objective tablet can be obtained. In addition, a desired tablet can be
obtained by appropriately changing the kind and/or amount of the present
compound and additives.

[0389]In order to evaluate a binding activity to GR, a receptor competitor
assay was carried out by a fluorescence polarization method. In the
assay, a GR competitor assay kit (manufactured by Invitrogen, cat No.
P2816) was used, and a procedure was carried out according to the
protocol attached to the kit. Hereinafter, the specific method will be
described.

[0393]After a test compound was dissolved in dimethylsulfoxide, the
resulting solution was diluted with GR screening buffer, whereby a 20
μM test compound solution was prepared.

(Test Method and Measurement Method)

[0394]1) The test compound solution was added in an amount of 25 μL
into each well of a 96-well plate, and then, 4×GS1 solution and
4×GR solution were added in an amount of 12.5 μL into each well,
respectively.

[0395]2) The plate was incubated in a dark place at room temperature for 2
to 4 hours.

[0396]3) By using a multimode plate reader, Analyst® HT (manufactured
by LJL Biosystems), fluorescence polarization of each well was measured.
As the blank, a well containing GR screening buffer in place of the test
compound and 4×GS1 solution was used.

[0397]4) The same procedure as that in the above 1) to 3) was carried out
except that GR screening buffer was used in place of the test compound
solution, and the obtained result was taken as the negative control.

[0398]5) The same procedure as that in the above 1) to 3) was carried out
except that 2 mM dexamethasone was used in place of the test compound
solution, and the obtained result was taken as the positive control.

(Calculation Equation of Gr Binding Ratio)

[0399]A GR binding ratio (%) was calculated from the following equation.

[0402]As is apparent from Table I, the present compound showed an
excellent GR binding activity. Accordingly, the present compound can be
used as a GR modulator, and is useful for a preventive or therapeutic
agent particularly for GR-related diseases, that is, metabolic disorders,
inflammatory diseases, autoimmune diseases, allergic diseases, central
nervous system diseases, cardiovascular diseases, homeostasis-related
diseases, glaucoma and the like.

INDUSTRIAL APPLICABILITY

[0403]1,2,3,4-tetrahydroquinoxaline derivative or the salt according to
the present invention has a binding activity to GR and is useful for GR
modulator of nonsteroidal compound.